Partially saturated nitrogen-containing heterocyclic compound

ABSTRACT

There are provided compounds having a superior PHD2 inhibitory effect that are represented by general formula (I′): 
     
       
         
         
             
             
         
       
         
         (in the above-mentioned general formula (I′), 
         W, Y, R 2 , R 3 , R 4 , and Y 4  are as described hereinabove), or pharmaceutically acceptable salts thereof.

TECHNICAL FIELD

The present invention relates to novel prolyl hydroxylase (hereinafter also referred to as PHD) inhibitors, in particular, prolyl hydroxylase 2 (hereinafter also referred to as PHD2) inhibitors.

BACKGROUND ART

Erythrocytes in the blood are responsible for oxygen transport throughout the body and play an important role in maintaining oxygen levels constant in vivo. If, on account of bleeding due to certain kinds of disease, as well as to accidents or surgical operations, the erythrocyte counts or hemoglobins level in the blood decrease, a sense of fatigue, dizziness, shortness of breath and other anemic symptoms will develop. In anemia, the entire body will be exposed to oxygen deficiency and under such hypoxic conditions, the living body performs a compensatory reaction, in which the hematopoietic factor erythropoietin (hereinafter also referred to as EPO) which promotes the formation of erythrocytes is produced primarily from the kidney to increase the erythrocyte and hemoglobin levels in the blood, thus helping to ameliorate anemia. However, in certain kinds of disease, this erythropoietic action of erythropoietin is impaired and chronic anemia persists. For example, in patients with renal failure who have disorder in the kidney, it is known that the above-described mechanism for erythropoietin production under hypoxic conditions fails to work properly, causing them to present with a type of anemia (renal anemia) which is characterized by reduced erythrocyte counts and hemoglobin levels (see Non-Patent Documents 1 and 2).

The treatment of renal anemia and the anemia that accompanies cancer chemotherapy or medication of patients with HIV infection is currently carried out by erythropoiesis stimulating agents (ESA) such as genetically recombinant human erythropoietin preparations. The ESA greatly contributes to improving a patient's quality of life by increasing the erythrocyte counts and hemoglobin levels sufficiently to ameliorate the symptoms that accompany anemia. On the other hand, however, the currently available ESAs are all biologics in the form of expensive injections, so it is desired to develop an orally administrable pharmaceutical drug for the treatment of anemia.

A recent study has reported that erythropoietin also has an action for protecting tissues such as hearts and brains placed under the hypoxic conditions that accompany anemia. Therefore, orally administrable ESA preparations have the potential to find a wide range of applications covering not only renal and other types of anemia that result from various causes but also a diversity of ischemic diseases (see Non-Patent Document 3).

A substance that may be mentioned as a factor that increases the production of erythropoietin is a hypoxia-inducible factor (hereinafter also referred to as HIF). The HIF is a transcription factor including an α-subunit the degradation of which is regulated by changes in oxygen density and a β-subunit that is expressed constantly. Prolyl hydroxylases (PHD-1, -2 and -3) are known as factors that regulate the degradation of HIF's α-subunit (HIF-α). Under normal oxygen pressure conditions, the proline residues of HIF-α are hydroxylated by these prolyl hydroxylases and the HIF-α is rapidly degraded by proteasome. Under hypoxic conditions, on the other hand, the activity of prolyl hydroxylases is lowered, so the degradation of HIF-α is suppressed, thus promoting the transcription of the erythropoietin and other HIF-responsive genes. Consequently, by inhibiting the prolyl hydroxylases, the stabilization of HIF-α is promoted, making it possible to increase the production of erythropoietin (see Non-Patent Documents 1, 2 and 4).

The compounds of the present invention provide means for inhibiting the activities of those prolyl hydroxylases to increase the amount of erythropoietin, thereby treating anemia. As another benefit, not only anemia but also various other ischemic diseases (e.g. brain stroke, myocardial infarction, and ischemic renal disorder) and diabetic complications (nephropathy, retinopathy, and neuropathy) can also be treated or prevented or improved or mitigated in symptoms by administering the compounds of the present invention (see Non-Patent Document 5).

Common PHD inhibitors reported to date include 4-hydroxyisoquinoline derivatives (see Patent Document 1), 5-hydroxy-3-oxo-2,3-dihydro-1H-pyrazole derivatives (see Patent Document 2), 4-hydroxy-2-oxo-1,2-dihydroquinoline derivatives (see Patent Document 3), 3-hydroxypyridine derivatives (see Patent Document 4), 2-oxo-2,3-dihydroindole derivatives (see Patent Document 5), etc. but compounds having the structures according to the present invention have not been disclosed. Also reported to date include are 6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydropyrimidine derivatives (see Patent Document 6), 4-hydroxy-6-oxo-1,6-dihydropyrimidine derivatives (see Patent Document 7), 5-hydroxy-3-oxo-2,3-dihydropyridazine derivatives (see Patent Document 8), 6-hydroxy-4-oxo-4H-1,3-dioxin derivatives (see Patent Document 9), 4-hydroxy-2-oxo-1,2,5,7-tetrahydrofluoro[3,4-b]pyridine derivatives (see Patent Document 10), 4-hydroxy-2-oxo-1,2-dihydropyridine derivatives (see Patent Documents 11 and 12), etc. but compounds having the structures according to the present invention have not been disclosed.

CITATION LIST Patent Documents

-   Patent Document 1: WO 2004/108681 -   Patent Document 2: WO 2006/114213 -   Patent Document 3: WO 2007/038571 -   Patent Document 4: US 2007/0299086 -   Patent Document 5: WO 2008/144266 -   Patent Document 6: WO 2007/150011 -   Patent Document 7: WO 2008/089051 -   Patent Document 8: WO 2008/089052 -   Patent Document 9: WO 2009/049112 -   Patent Document 10: WO 2009/108496 -   Patent Document 11: WO 2009/158315 -   Patent Document 12: WO 2010/025087

Non-Patent Documents

-   Non-Patent Document 1: American Journal of Physiology-Renal     Physiology, 2010, 299, F1-13 -   Non-Patent Document 2: American Journal of Physiology-Renal     Physiology, 2010, 298, F1287-1296 -   Non-Patent Document 3: The Journal of Physiology, 2011, 589,     1251-1258 -   Non-Patent Document 4: Expert Opinion on Therapeutic Patents, 2010,     20, 1219-1245 -   Non-Patent Document 5: Diabetes, Obesity and Metabolism, 2008, 10,     1-9

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide superior PHD 2 inhibitors.

Solution to Problem

The present inventors conducted intensive studies with a view to attaining the above-stated object and found as a result that compounds represented by the following general formula (I) or (I′) have a superior PHD 2 inhibitory effect.

Briefly, the present invention is directed to:

(1) providing a compound represented by the following general formula (I′)

(wherein in formula (I′), W represents the formula —CR¹⁵R¹⁶—, the formula —CR¹¹R¹²CR¹³R¹⁴—, or the formula —CH₂CR¹⁷R¹⁸CH₂—; R¹⁵ represents a hydrogen atom, C₁₋₄ alkyl, or phenyl; represents a hydrogen atom or C₁₋₄ alkyl; provided that R¹⁵ and R¹⁶, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane; R¹¹ represents a hydrogen atom, a fluorine atom, C₁₋₄ alkyl, or phenyl; R¹² represents a hydrogen atom, a fluorine atom, or C₁₋₄ alkyl; provided that R¹¹ and R¹², together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom; R¹³ represents a hydrogen atom, carbamoyl, C₁₋₄ alkyl (the C₁₋₄ alkyl is optionally substituted by one group selected from the group consisting of hydroxy, C₁₋₃ alkoxy, and di-C₁₋₃ alkylamino), halo-C₁₋₄ alkyl, phenyl, pyridyl, benzyl, or phenethyl; R¹⁴ represents a hydrogen atom, C₁₋₄ alkyl, or halo-C₁₋₄ alkyl; provided that R¹³ and R¹⁴, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane, a 4- to 8-membered saturated heterocycle containing an oxygen atom, or a 4- to 8-membered saturated heterocycle containing a nitrogen atom (the 4- to 8-membered saturated heterocycle containing a nitrogen atom is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of methyl, benzyl, phenylcarbonyl, and oxo); provided that said R¹² and R¹³, together with the adjacent carbon atoms, optionally form C₃₋₈ cycloalkane; R¹⁷ represents a hydrogen atom or C₁₋₄ alkyl; R¹⁸ represents a hydrogen atom or C₁₋₄ alkyl; provided that R¹⁷ and R¹⁸, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane; Y represents a single bond or C₁₋₆ alkanediyl (the C₁₋₆ alkanediyl is optionally substituted by one hydroxy, and one of the carbon atoms in the C₁₋₆ alkanediyl is optionally substituted by C₃₋₆ cycloalkane-1,1-diyl); R² represents a hydrogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl {the C₃₋₈ cycloalkyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl (the C₁₋₆ alkyl is optionally substituted by one phenyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and halo-C₁₋₆ alkyl), C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), and pyridyl (the pyridyl is optionally substituted by one halogen atom)], C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl)}, phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α3 of substituents), naphthyl, indanyl, tetrahydronaphthyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl [the pyrazolyl, imidazolyl, isoxazolyl, and oxazolyl are optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl and phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], thiazoyl [the thiazoyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), and morpholino], pyridyl (the pyridyl is optionally substituted by one or two groups which are the same or different and are selected from group α5 of substituents), pyridazinyl, pyrimidinyl, pyrazinyl [the pyridazinyl, pyrimidinyl, and pyrazinyl are optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl), and phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl)], benzothiophenyl, quinolyl, methylenedioxyphenyl (the methylenedioxyphenyl is optionally substituted by one or two fluorine atoms), 4- to 8-membered saturated heterocyclyl containing a nitrogen atom [the 4- to 8-membered saturated heterocyclyl containing a nitrogen atom is optionally substituted by one group selected from the group consisting of pyrimidinyl, phenyl-C₁₋₃ alkyl, C₃₋₈ cycloalkyl-C₁₋₃ alkylcarbonyl, and phenyl-C₁₋₃ alkoxycarbonyl], or the following formula (I″)

[Formula 2]

—CONR⁵CH₂—R⁶  (I″)

[wherein in formula (I″), R⁵ represents a hydrogen atom or C₁₋₃ alkyl, and R⁶ represents phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and phenyl)], group α3 of substituents consists of hydroxy, cyano, carboxy, a halogen atom, C₁₋₆ alkyl {the C₁₋₆ alkyl is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl)], phenoxy (the phenoxy is optionally substituted by one C₁₋₆ alkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl and halo-C₁₋₆ alkyl)}, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one or two halogen atoms), C₃₋₈ cycloalkenyl (the C₃₋₈ cycloalkenyl is optionally substituted by one or two halogen atoms), phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α4 of substituents), thienyl (the thienyl is optionally substituted by one C₁₋₆ alkyl), pyrazolyl (the pyrazolyl is optionally substituted by one C₁₋₆ alkyl), isoxazolyl, thiazoyl (the thiazoyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, amino, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and C₁₋₆ alkylsulfonyl), pyrimidinyl (the pyrimidinyl is optionally substituted by one amino), quinolyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, carbamoyl, C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of hydroxy, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, hale-C₁₋₆ alkoxy, and di-C₁₋₆ alkylamino), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), oxazolyl (the oxazolyl is optionally substituted by one or two C₁₋₆ alkyls), pyrazolyl (the pyrazolyl is optionally substituted by one or two C₁₋₆ alkyls), thiazoyl (the thiazoyl is optionally substituted by one C₁₋₆ alkyl), indazolyl (the indazolyl is optionally substituted by one C₁₋₆ alkyl), benzotriazolyl, imidazothiazoyl, and di-C₁₋₆ alkylamino], halo-C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and C₃₋₈ cycloalkyl), pyrimidinyloxy, piperazinyl (the piperazinyl is optionally substituted by one C₁₋₆ alkyl), mono-C₁₋₆ alkylaminocarbonyl (the C₁₋₆ alkyl in the mono-C₁₋₆ alkylaminocarbonyl is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, di-C₁₋₆ alkylamino, pyridyl, phenyl, and 2-oxopyrrolidinyl), di-C₁₋₆ alkylaminocarbonyl (where the two C₁₋₆ alkyls in the di-C₁₋₆ alkylaminocarbonyl, together with the adjacent nitrogen atom, optionally form a 4- to 8-membered saturated heterocycle containing a nitrogen atom), C₁₋₆ alkylsulfanyl, and C₁₋₆ alkylsulfonyl; group α4 of substituents consists of carboxy, cyano, hydroxy, sulfamoyl, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, di-C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkylsulfonyl, mono-C₁₋₆ alkylaminosulfonyl (the C₁₋₆ alkyl in the mono-C₁₋₆ alkylaminosulfonyl is optionally substituted by one hydroxy), and di-C₁₋₆ alkylaminosulfonyl; group α5 of substituents consists of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl) and phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], halo-C₁₋₆ alkoxy, phenyl (the phenyl is optionally substituted by one group selected from group α6 of substituents), pyridyl, phenoxy [the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one phenyl), and halo-C₁₋₆ alkoxy], pyridyloxy (the pyridyloxy is optionally substituted by one C₁₋₆ alkyl), and phenylsulfanyl (the phenylsulfanyl is optionally substituted by one halogen atom); group α6 of substituents consists of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy; Y⁴ represents C₁₋₄ alkanediyl; R³ represents a hydrogen atom or methyl; R⁴ represents —COOH, —CONHOH, or tetrazolyl); or a pharmaceutically acceptable salt thereof.

(2) In another mode, the present invention is directed to providing the compound according to (1) wherein in the aforementioned general formula (I′),

Y⁴ is methanediyl, R³ is a hydrogen atom,

R⁴ is —COOH,

or a pharmaceutically acceptable salt thereof.

(3) In another mode, the present invention is directed to providing the compound according to (2) wherein in the aforementioned general formula (I′),

W is the formula —CR¹⁵R¹⁶—, and the compound is represented by general formula (I′-1):

(I′-1) (wherein in formula (I′-1)

R¹⁵ is a hydrogen atom, C₁₋₄ alkyl, or phenyl, R¹⁶ is a hydrogen atom or C₁₋₄ alkyl, provided that R¹⁵ and R¹⁶, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane), or a pharmaceutically acceptable salt thereof.

(4) In another mode, the present invention is directed to providing the compound according to (2) wherein in the aforementioned general formula (I′),

W is the formula —CR¹¹R¹²CR¹³R¹⁴—, and the compound is represented by general formula (I′-2):

(wherein in formula (I′-2), R¹¹ is a hydrogen atom, a fluorine atom, C₁₋₄ alkyl, or phenyl, R¹² is a hydrogen atom, a fluorine atom, or C₁₋₄ alkyl, provided that R¹¹ and R¹², together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom; R¹³ is a hydrogen atom, carbamoyl, C₁₋₄ alkyl (the C₁₋₄ alkyl is optionally substituted by one group selected from the group consisting of hydroxy, C₁₋₃ alkoxy, and di-C₁₋₃ alkylamino), halo-C₁₋₄ alkyl, phenyl, pyridyl, benzyl, or phenethyl; R¹⁴ is a hydrogen atom, C₁₋₄ alkyl, or halo-C₁₋₄ alkyl, provided that R¹³ and R¹⁴, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane, a 4- to 8-membered saturated heterocycle containing an oxygen atom, or a 4- to 8-membered saturated heterocycle containing a nitrogen atom (the 4- to 8-membered saturated heterocycle containing a nitrogen atom is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of methyl, benzyl, phenylcarbonyl, and oxo), provided that the aforementioned R¹² and R¹³, together with the adjacent carbon atoms, optionally form C₃₋₈ cycloalkane), or a pharmaceutically acceptable salt thereof.

(5) In another mode, the present invention is directed to providing the compound according to (4) wherein in the aforementioned general formula (I′-2),

Y is a single bond or C₁₋₆ alkanediyl (one of the carbon atoms in the C₁₋₆ alkanediyl is optionally substituted by C₃₋₆ cycloalkane-1,1-diyl), R² is C₃₋₈ cycloalkyl {the C₃₋₈ cycloalkyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl (the C₁₋₆ alkyl is optionally substituted by one phenyl), phenyl (the phenyl is optionally substituted by one halo-C₁₋₆ alkyl), C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), and pyridyl (the pyridyl is optionally substituted by one halogen atom)], C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl)}, phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from the aforementioned group α3 of substituents), naphthyl, indanyl, tetrahydronaphthyl, pyrazolyl [the pyrazolyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl and phenyl (the phenyl is optionally substituted by one C₁₋₆ alkyl)], imidazolyl (the imidazolyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl and phenyl), isoxazolyl [the isoxazolyl is optionally substituted by one phenyl (the phenyl is optionally substituted by one halogen atom)], oxazolyl (the oxazolyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl and phenyl), thiazoyl (the thiazoyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl, phenyl, and morpholino), pyridyl (the pyridyl is optionally substituted by one or two groups which are the same or different and are selected from the aforementioned group α5 of substituents), pyridazinyl [the pyridazinyl is optionally substituted by one C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl)], pyrimidinyl [the pyrimidinyl is optionally substituted by one group selected from the group consisting of halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, and phenoxy (the phenoxy is optionally substituted by one C₁₋₆ alkyl)], pyrazinyl [the pyrazinyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by C₃₋₈ cycloalkyl) and phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl)], benzothiophenyl, quinolyl, or methylenedioxyphenyl (the methylenedioxyphenyl is optionally substituted by one or two fluorine atoms), or a pharmaceutically acceptable salt thereof.

(6) In another mode, the present invention is directed to providing the compound according to (5) wherein in the aforementioned general formula (I′-2),

R¹¹ is a hydrogen atom, R¹² is a hydrogen atom, R¹³ is a hydrogen atom, R¹⁴ is a hydrogen atom, Y is methanediyl,

R² is

phenyl {the phenyl is substituted by one group selected from the group consisting of phenyl [the phenyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of carboxy, cyano, hydroxy, sulfamoyl, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, di-C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkylsulfonyl, mono-C₁₋₆ alkylaminosulfonyl (the C₁₋₆ alkyl in the mono-C₁₋₆ alkylaminosulfonyl is optionally substituted by one hydroxy), and di-C₁₋₆ alkylaminosulfonyl], pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, amino, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ alkylsulfonyl), phenoxy (the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and C₃₋₈ cycloalkyl), and may further be substituted by one halogen atom}; pyridyl {the pyridyl is substituted by one group selected from the group consisting of phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyl, phenoxy [the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one phenyl), and halo-C₁₋₆ alkoxy], and pyridyloxy (the pyridyloxy is optionally substituted by one C₁₋₆ alkyl), and may further be substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl}; or pyrazinyl which is substituted by one phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl), or a pharmaceutically acceptable salt thereof.

(7) In another mode, the present invention is directed to providing the following compound according to (1):

-   N-{[4-hydroxy-2-oxo-1-(4-phenoxybenzyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; -   N-[(4-hydroxy-1-{[6-(4-methylphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-({4-hydroxy-2-oxo-1-[(6-phenoxy-3-pyridinyl)methyl]-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; -   N-({1-[4-(4-fluorophenoxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; -   N-({4-hydroxy-1-[4-(4-methylphenoxyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; -   N-[(1-{[6-(4-cyanophenoxy)-3-pyridinyl]methyl{-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-(4-hydroxy-2-oxo-1-[4-(2-pyrimidinyloxy)benzyl]-1,2,5,6-tetrahydro-3-pyridinyl     carbonyl)glycine; -   N-[(1-[6-(4-fluorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-[6-(4-chlorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-{[4-hydroxy-2-oxo-1-({6-[4-(trifluoromethyl)phenoxy]-3-pyridinyl}methyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; -   N-[(4-hydroxy-1-{[6-(3-methylphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-{[6-(3-fluorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-({4-hydroxy-1-[4-(3-methylphenoxyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; -   N-({1-[4-(3-fluorophenoxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; -   N-[(1-{[5-(4-fluorophenoxy)-2-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(4-hydroxy-1-{[5-(4-methylphenoxy)-2-pyridinyl]methyl-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-({1-[4-(4-chlorophenoxyl)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; -   N-[(4-hydroxy-1-{4-[(6-methyl-3-pyridinyl)oxy]benzyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-[6-(2-fluorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(4-hydroxy-1-{[6-(2-methylphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-({1-[4-(2-fluorophenoxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; -   N-({4-hydroxy-1-[4-(2-methylphenoxyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; -   N-[(1-{[6-(3-chlorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-{[4-hydroxy-2-oxo-1-({6-[3-(trifluoromethyl)phenoxy]-3-pyridinyl]methyl}-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; -   N-({4-hydroxy-1-[4-(3-methoxyphenoxy)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; -   N-{[4-hydroxy-2-oxo-1-({6-[3-(trifluoromethoxy)phenoxy]-3-pyridinyl}methyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; -   N-[(1-{4-[(5-fluoro-2-pyridinyl)oxy]benzyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-{4-[(5-chloro-2-pyridinyl)oxy]benzyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-{[6-(4-cyclopropylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(4-hydroxy-1-{4-[(5-methyl-2-pyridinyl)oxy]benzyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-{[4-hydroxy-2-oxo-1-(4-{[5-(trifluoromethyl)-2-pyridinyl]oxy}benzyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; -   N-{[4-hydroxy-1-({5-methyl-6-[(6-methyl-3-pyridinyl)oxy]-3-pyridinyl}methyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; -   N-[(1-{[5-(4-chlorophenoxy)-2-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(4-hydroxy-1-{[6-(3-methoxyphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-{4-[(6-chloro-3-pyridinyl)oxy]benzyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-{[4-hydroxy-2-oxo-1-({5-[4-(trifluoromethyl)phenoxy]-2-pyridinyl}methyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; -   N-[4-hydroxy-2-oxo-1-(4-{[6-(trifluoromethyl)-3-pyridinyl]oxy}benzyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl     glycine; -   N-[(1-{[6-(3-chloro-4-methylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-{[6-(3-fluoro-4-methylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-{[6-(4-fluoro-3-methylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-{[6-(4-ethylphenoxy)-3-pyridinyl]methyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl}glycine; -   N-[(4-hydroxy-2-oxo-1-{[6-(4-propylphenoxy)-3-pyridinyl]methyl}-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(4-hydroxy-1-{[6(4-isopropylphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(4-hydroxy-1-{-(4-methylphenoxy)-2-pyrazinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-({1-[4-(3,4-dimethylphenoxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl     carbonyl)glycine; -   N-[(1-{[5-chloro-6-(4-methylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-[5-fluoro-6-(4-methylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-{4-[(5-cyclopropyl-2-pyridinyl)oxy]benzyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(4-hydroxy-1-{[2-(4-methylphenoxy)-5-pyrimidinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-{[6-(4-chlorophenoxy)-5-methyl-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; -   N-[(1-{[5-(4-chlorophenoxy)-2-pyrazinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine;     or -   N-[(1-{[5-(4-cyclopropylphenoxy)-2-pyrazinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine,     or a pharmaceutically acceptable salt thereof.

(8) In another mode, the present invention is directed to providing a compound having the aforementioned general formula (I′), wherein

W is the formula —CR¹¹R¹²cR¹³R¹⁴, and the compound is represented by general formula (I):

(wherein in formula (I), R¹¹ is a hydrogen atom, C₁₋₄ alkyl, or phenyl, R¹² is a hydrogen atom or C₁₋₄ alkyl, provided that R¹¹ and R¹², together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom; R¹³ is a hydrogen atom, C₁₋₄ alkyl, halo-C₁₋₄ alkyl, phenyl, benzyl, or phenethyl, R¹⁴ is a hydrogen atom or C₁₋₄ alkyl, provided that R¹³ and R¹⁴, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom, provided that the aforementioned R¹² and R¹³, together with the adjacent carbon atoms, optionally form C₃₋₈ cycloalkane; Y is a single bond or C₁₋₆ alkanediyl (one of the carbon atoms in the C₁₋₆ alkanediyl is optionally substituted by C₃₋₆ cycloalkane-1,1-diyl); R² is C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one group selected from the group consisting of phenyl and benzyl), phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α1 of substituents), naphthyl, indanyl, tetrahydronaphthyl, pyrazolyl [the pyrazolyl is substituted by one phenyl (the phenyl is optionally substituted by one C₁₋₆ alkyl) and may further be substituted by one C₁₋₆ alkyl], imidazolyl (the imidazolyl is substituted by one phenyl), isoxazolyl [the isoxazolyl is substituted by one phenyl (the phenyl is optionally substituted by one halogen atom)], oxazolyl (the oxazolyl is substituted by one phenyl and may further be substituted by one C₁₋₆ alkyl), thiazoyl (the thiazoyl is substituted by one phenyl), pyridyl [the pyridyl is substituted by one group selected from the group consisting of phenyl, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), and phenylsulfanyl (the phenylsulfanyl is optionally substituted by one halogen atom)], pyrimidinyl (the pyrimidinyl is substituted by one group selected from the group consisting of cyclohexyl and phenyl), benzothiophenyl, quinolyl, or methylenedioxyphenyl (the methylenedioxyphenyl is optionally substituted by one or two fluorine atoms); group α1 of substituents consists of a halogen atom, C₁₋₆ alkyl {the C₁₋₆ alkyl is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl, and C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl)]}, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α2 of substituents), thienyl, pyrazolyl (the pyrazolyl is optionally substituted by one C₁₋₆ alkyl), isoxazolyl, thiazoyl (the thiazoyl is optionally substituted by one or two C₁₋₆ alkyls), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), quinolyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl and phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], halo-C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and halo-C₁₋₆ alkyl), and C₁₋₆ alkylsulfanyl; group α2 of substituents consists of a halogen atom, cyano, hydroxy, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, and di-C₁₋₆ alkylaminosulfonyl), or a pharmaceutically acceptable salt thereof.

(9) In another mode, the present invention is directed to providing a medicine comprising the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof as an active ingredient.

(10) In another mode, the present invention is directed to providing a PHD2 inhibitor comprising the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof as an active ingredient.

(11) In another mode, the present invention is directed to providing an EPO production promoter comprising the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof as an active ingredient.

(12) In another mode, the present invention is directed to providing a drug for preventing or treating anemia comprising the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof as an active ingredient.

Advantageous Effects of Invention

The present invention has made it possible to provide compounds having a superior PHD2 inhibitory effect.

DESCRIPTION OF EMBODIMENTS

The present invention provides compounds having a superior PHD2 inhibitory effect that are represented by general formula (I) or (I′), or pharmaceutically acceptable salts thereof

On the following pages, the compounds of the present invention are described in greater detail but it should be understood that the present invention is by no means limited to the following illustrations.

As used herein, symbol “n” refers to normal, “s” or “sec”, secondary, “t” or “tert”, tertiary, “c”, cyclo, “o”, ortho, “m”, meta, and “p”, para.

The “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The “C₁₋₃ alkyl” refers to linear or branched alkyl having one to three carbon atoms. Specifically, methyl, ethyl, n-propyl, and isopropyl are referred to.

The “C₁₋₄ alkyl” refers to linear or branched alkyl having one to four carbon atoms. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl are referred to.

The “C₁₋₆ alkyl” refers to linear or branched alkyl having one to six carbon atoms, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-methylbutyl, n-hexyl, isohexyl, etc.

The “halo-C₁₋₄ alkyl” refers to linear or branched alkyl having one to four carbon atoms, with substitution by a halogen atom. The number of substitutions by a halogen atom is preferably from one to three, and a preferred halogen atom is a fluorine atom. Examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl, etc.

The “halo-C₁₋₆ alkyl” refers to linear or branched alkyl having one to six carbon atoms, with substitution by a halogen atom. The number of substitutions by a halogen atom is preferably from one to five, and a preferred halogen atom is a fluorine atom. Examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2-fluoroethyl, 2-fluoro-2-methylpropyl, 2,2-difluoropropyl, 1-fluoro-2-methylpropan-2-yl, 1,1-difluoro-2-methylpropan-2-yl, 1-fluoropentyl, 1-fluorohexyl, etc.

The “C₃₋₆ cycloalkane” refers to cyclic alkane having three to six carbon atoms. Examples include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

The “C₃₋₈ cycloalkane” refers to cyclic alkane having three to eight carbon atoms. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

The “C₃₋₈ cycloalkyl” refers to cyclic alkyl having three to eight carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The “C₃₋₈ cycloalkenyl” refers to cyclic alkenyl having three to eight carbon atoms. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

The “4- to 8-membered saturated heterocycle containing an oxygen atom” refers to a 4- to 8-membered monocylic saturated heterocycle containing one oxygen atom in the ring. Examples include oxetane, tetrahydrofuran, tetrahydropyran, etc.

The “4- to 8-membered saturated heterocycle containing a nitrogen atom” refers to a 4to 8-membered monocylic saturated heterocycle containing one nitrogen atom in the ring. Examples include azetidine, pyrrolidine, piperidine, etc.

The “4- to 8-membered saturated heterocyclyl containing a nitrogen atom” refers to a 4to 8-membered monocytic saturated heterocyclic group containing one nitrogen atom in the ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, etc.

The “C₁₋₃ alkoxy” refers to linear or branched alkoxy having one to three carbon atoms. Specifically, methoxy, ethoxy, n-propoxy, and isopropoxy are referred to.

The “C₁₋₆ alkoxy” refers to linear or branched alkoxy having one to six carbon atoms. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, n-hexyloxy, isohexyloxy, etc.

The “halo-C₁₋₆ alkoxy” refers to linear or branched alkoxy having one to six carbon atoms, with substitution by a halogen atom. The number of substitutions by a halogen atom is preferably from one to five, and a preferred halogen atom is a fluorine atom. Examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoropropoxy, 1,3-difluoropropan-2-yloxy, 2-fluoro-2-methylpropoxy, 2,2-difluoropropoxy, 1-fluoro-2-methylpropan-2-yloxy, 1,1-difluoro-2-methylpropan-2-yloxy, 4,4,4-trifluorobutoxy, etc.

The “C₁₋₆ alkenyloxy” refers to a group of such a structure that oxy is bound to linear or branched alkenyl having two to six carbon atoms. Examples include ethenyloxy, (E)-prop-1-en-1-yloxy, (Z)-prop-1-en-1-yloxy, prop-2-en-1-yloxy, (Z)-but-2-en-1-yloxy, (Z)-pent-3-en-1-yloxy, (Z)-hex-4-en-1-yloxy, (Z)-hept-5-en-1-yloxy, and (Z)-oct-6-en-1-yloxy, etc.

The “C₃₋₈ cycloalkoxy” refers to cyclic alkoxy having three to eight carbon atoms. Examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

The “di-C₁₋₃ alkylamino” refers to amino having the aforementioned “C₁₋₃ alkyl” as two substituents which are the same or different. Examples include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, methyl(n-propyl)amino, etc.

The “di-C₁₋₆ alkylamino” refers to amino having the aforementioned “C₁₋₆ alkyl” as two substituents which are the same or different. Examples include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino, methyl(n-propyl)amino, etc.

The “C₁₋₆ alkylcarbonyl” refers to a group of such a structure that carbonyl is bound to the aforementioned “C₁₋₆ alkyl”. Examples include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbony, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, 2-methylbutylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl, etc.

The “mono-C₁₋₆ alkylaminocarbonyl” refers to a group of such a structure that carbonyl is bound to amino having the aforementioned “C₁₋₆ alkyl” as a single substituent. Examples include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, etc.

The “di-C₁₋₆ alkylaminocarbonyl” refers to a group of such a structure that carbonyl is bound to amino having the aforementioned “C₁₋₆ alkyl” as two substituents which are the same or different. Examples include dimethylaminocarbonyl, di(n-propyl)aminocarbonyl, di(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, methyl(n-propyl)aminocarbonyl, etc.

The two C₁₋₆ alkyls in the di-C₁₋₆ alkylaminocarbonyl, together with the adjacent nitrogen atom, may optionally form a 4- to 8-membered saturated heterocycle containing a nitrogen atom.

The “C₁₋₆ alkylsulfanyl” refers to a group of such a structure that sulfanyl is bound to the aforementioned “C₁₋₆ alkyl”. Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropyl sulfanyl, isobutylsulfanyl, n-hexylsulfanyl, etc.

The “C₁₋₆ alkylsulfonyl” is a group of such a structure that sulfonyl is bound to the aforementioned “C₁₋₆ alkyl”. Examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, isobutylsulfonyl, n-hexylsulfonyl, etc.

The “mono-C₁₋₆ alkylaminosulfonyl” refers to a group of such a structure that sulfonyl is bound to amino having the aforementioned “C₁₋₆ alkyl” as a single substituent. Examples include methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, n-butylaminosulfonyl, isobutylaminosulfonyl, sec-butylaminosulfonyl, tert-butylaminosulfonyl, n-pentylaminosulfonyl, n-hexylaminosulfonyl, etc.

The “di-C₁₋₆ alkylaminosulfonyl” refers to a group of such a structure that sulfonyl is bound to amino having the aforementioned “C₁₋₆ alkyl” as two substituents which are the same or different. Examples include dimethylaminosulfonyl, diethylaminosulfonyl, di(n-propyl)aminosulfonyl, di(isopropyl)aminosulfonyl, ethylmethylaminosulfonyl, methyl(n-propyl)aminosulfonyl, isopropyl(methyl)aminosulfonyl, etc.

The “C₁₋₄ alkanediyl” refers to a divalent hydrocarbon group of such a structure that one hydrogen atom has been removed from an alkyl group having one to four carbon atoms. Examples include methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,4-diyl, 2-methylpropane-1,2-diyl, etc. Among these, methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-1,3-diyl, and propane-2,2-diyl are C₁₋₃ alkanediyls.

The “C₁₋₆ alkanediyl” refers to a divalent hydrocarbon group of such a structure that one hydrogen atom has been removed from an alkyl group having one to six carbon atoms. Examples include methanediyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,4-diyl, 2-methylpropane-1,2-diyl, pentane-1,5-diyl, hexane-1,6-diyl, etc.

The “C₃₋₆ cycloalkane-1,1-diyl” refers to a divalent cyclic hydrocarbon group of such a structure that one hydrogen atom has been removed from a cycloalkyl group having three to six carbon atoms. Examples include cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, and cyclohexane-1,1-diyl.

The “phenyl-C₁₋₃ alkyl” refers to the aforementioned “C₁₋₃ alkyl” having a phenyl group as a substituent. Examples include benzyl, phenethyl, and phenylpropyl.

The “C₃₋₈ cycloalkyl-C₁₋₃ alkylcarbonyl” refers to a group of such a structure that the aforementioned cycloalkyl group having three to eight carbon atoms binds a carbonyl group via the aforementioned C₁₋₃ alkyl. Examples include cyclopropylmethylcarbonyl, cyclopropylethylcarbonyl, cyclobutylmethylcarbonyl, cyclopentylmethylcarbonyl, cyclohexylmethylcarbonyl, etc.

The “phenyl-C₁₋₃ alkoxycarbonyl” refers to a group of such a structure that a phenyl group binds a carbonyl group via the aforementioned C₁₋₃ alkoxy. Examples include phenylmethoxycarbonyl, phenylethoxycarbonyl, and phenylpropoxycarbonyl.

Preferred modes of the compounds of the present invention are as follows.

A preferred case of W is the formula —CR¹⁵R¹⁶— or the formula —CR¹¹R¹²cR¹³R¹⁴—.

When W represents the formula —CR¹⁵R¹⁶—,

one preferred case of R¹⁵ is a hydrogen atom or C₁₋₄ alkyl, with a more preferred case of R¹⁵ being a hydrogen atom or methyl, and an even more preferred case of R¹⁵ being a hydrogen atom;

one preferred case of R¹⁶ is a hydrogen atom or C₁₋₄ alkyl, with a more preferred case of R¹⁶ being a hydrogen atom or methyl, and an even more preferred case of R¹⁶ being a hydrogen atom;

another preferred case of R¹⁵ and R¹⁶ is such that the R¹⁵ and R¹⁶, together with the adjacent carbon atom, form C₃₋₈ cycloalkane, with a more preferred case of R¹⁵ and R¹⁶ being such that the R¹⁵ and R¹⁶, together with the adjacent carbon atom, form cyclobutane, cyclopentane, or cyclohexane.

When W represents the formula —CR¹¹R¹²cR¹³R¹⁴—,

one preferred case of R¹¹ is a hydrogen atom or C₁₋₄ alkyl, with a more preferred case of R¹¹ being a hydrogen atom or methyl, and an even more preferred case of R¹¹ being a hydrogen atom;

one preferred case of R is a hydrogen atom or C₁₋₄ alkyl, with a more preferred case of R¹² being a hydrogen atom or methyl, and an even more preferred case of R¹² being a hydrogen atom;

another preferred case of R¹¹ and R¹² is such that the R¹¹ and R¹², together with the adjacent carbon atom, form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom, with a more preferred case of R¹¹ and R¹² being such that the R¹¹ and R¹², together with the adjacent carbon atom, form C₃₋₆ cycloalkane, and an even more preferred case of R¹¹ and R¹² being such that the R¹¹ and R¹², together with the adjacent carbon atom, form cyclopropane;

one preferred case of R¹³ is a hydrogen atom, C₁₋₄ alkyl, or halo-C₁₋₄ alkyl, with a more preferred case of R¹³ being a hydrogen atom or methyl, and an even more preferred case of R¹³ being a hydrogen atom;

one preferred case of R¹⁴ is a hydrogen atom or C₁₋₄ alkyl, with a more preferred case of R¹⁴ being a hydrogen atom or methyl, and an even more preferred case of R¹⁴ being a hydrogen atom;

another preferred case of R¹³ and R¹⁴ is such that the R¹³ and R¹⁴, together with the adjacent carbon atom, form C₃₋₈ cycloalkane, a 4- to 8-membered saturated heterocycle containing an oxygen atom, or a 4- to 8-membered saturated heterocycle containing a nitrogen atom (wherein the 4- to 8-membered saturated heterocycle containing a nitrogen atom is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of methyl, benzyl, phenylcarbonyl, and oxo), with a more preferred case of R¹³ and R¹⁴ being such that the R¹³ and R¹⁴, together with the adjacent carbon atom, form C₃₋₆ cycloalkane, an even more preferred case of R¹³ and R¹⁴ being such that the R¹³ and R¹⁴, together with the adjacent carbon atom, form cyclopropane, cyclobutane, cyclopentane, or cyclohexane, and a particularly preferred case of R¹³ and R¹⁴ being such that the R¹³ and R¹⁴, together with the adjacent carbon atom, form cyclopropane.

A preferred case of Y is a single bond or C₁₋₆ alkanediyl (one of the carbon atoms in the C₁₋₆ alkanediyl is optionally substituted by C₃₋₆ cycloalkane-1,1-diyl), with a more preferred case of Y being a single bond, methanediyl, ethane-1,1-diyl, propane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, or ethane-1,2-diyl, with an even more preferred case of Y being a single bond or methanediyl, and a particularly preferred case of Y being methanediyl.

Preferred modes of R² are described below under (1) to (4).

(1) A preferred case of R² is C₃₋₈ cycloalkyl{the C₃₋₈ cycloalkyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl (the C₁₋₆ alkyl is optionally substituted by one phenyl), phenyl (the phenyl is optionally substituted by one halo-C₁₋₆ alkyl), C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), and pyridyl (the pyridyl is optionally substituted by one halogen atom)], C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl)}, phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α3 of substituents), indanyl, isoxazolyl [the isoxazolyl is optionally substituted by one phenyl (the phenyl is optionally substituted by one halogen atom)], oxazolyl (the oxazolyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl and phenyl), thiazoyl (the thiazoyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl, phenyl, and morpholino), pyridyl (the pyridyl is optionally substituted by one or two groups which are the same or different and are selected from the aforementioned group α5 of substituents), pyrimidinyl [the pyrimidinyl is optionally substituted by one group selected from the group consisting of halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, and phenoxy (the phenoxy is optionally substituted by one C₁₋₆ alkyl)], pyrazinyl [the pyrazinyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl) and phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl)], or benzothiophenyl;

(2) A more preferred case of R² is

C₃₋₈ cycloalkyl {the C₃₋₈ cycloalkyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of phenyl (the phenyl is optionally substituted by one halo-C₁₋₆ alkyl), C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), and pyridyl (the pyridyl is optionally substituted by one halogen atom)], phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl)}; phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl {the C₁₋₆ alkyl is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl)], phenoxy (the phenoxy is optionally substituted by one C₁₋₆ alkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl and halo-C₁₋₆ alkyl)}, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one or two halogen atoms), phenyl [the phenyl is optionally substituted by one to three groups which are the same or different and are selected from the group consisting of carboxy, cyano, hydroxy, sulfamoyl, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, di-C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkylsulfonyl, mono-C₁₋₆ alkylaminosulfonyl (the C₁₋₆ alkyl of the mono-C₁₋₆ alkylaminosulfonyl is optionally substituted by one hydroxy), and di-C₁₋₆ alkylaminosulfonyl], thienyl (the thienyl is optionally substituted by one C₁₋₆ alkyl), pyrazolyl (the pyrazolyl is optionally substituted by one C₁₋₆ alkyl), isoxazolyl, thiazoyl (the thiazoyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, amino, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and C₁₋₆ alkylsulfonyl), pyrimidinyl (the pyrimidinyl is optionally substituted by one amino), quinolyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of hydroxy, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and di-C₁₋₆ alkylamino), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), oxazolyl (the oxazolyl is optionally substituted by one or two C₁₋₆ alkyls), pyrazolyl (the pyrazolyl is optionally substituted by one or two C₁₋₆ alkyls), thiazoyl (the thiazoyl is optionally substituted by one C₁₋₆ alkyl), indazolyl (the indazolyl is optionally substituted by one C₁₋₆ alkyl), benzotriazolyl, imidazothiazoyl, and di-C₁₋₆ alkylamino], halo-C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and C₃₋₈ cycloalkyl), C₁₋₆ alkylsulfanyl, and C₁₋₆ alkylsulfonyl); pyridyl {the pyridyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], halo-C₁₋₆ alkoxy, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyl, phenoxy [the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one phenyl), and halo-C₁₋₆ alkoxy], and pyridyloxy (the pyridyloxy is optionally substituted by one C₁₋₆ alkyl)}; or pyrazinyl [the pyrazinyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl) and phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl)];

(3) An even more preferred case of R² is

phenyl {the phenyl is substituted by one group selected from the group consisting of phenyl [the phenyl is optionally substituted by one to three groups which are the same or different and are selected from the group consisting of carboxy, cyano, hydroxy, sulfamoyl, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, di-C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkylsulfonyl, mono-C₁₋₆ alkylaminosulfonyl (the C₁₋₆ alkyl of the mono-C₁₋₆ alkylaminosulfonyl is optionally substituted by one hydroxy), and di-C₁₋₆ alkylaminosulfonyl], pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, amino, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and C₁₋₆ alkylsulfonyl), C₁₋₆ alkoxy [the C₁₋₆ alkoxy is substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of hydroxy, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and di-C₁₋₆ alkylamino), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), oxazolyl (the oxazolyl is optionally substituted by one or two C₁₋₆ alkyls), pyrazolyl (the pyrazolyl is optionally substituted by one or two C₁₋₆ alkyls), thiazoyl (the thiazoyl is optionally substituted by one C₁₋₆ alkyl), indazolyl (the indazolyl is optionally substituted by one C₁₋₆ alkyl), benzotriazolyl, imidazothiazoyl, and di-C₁₆ alkylamino], halo-C₁₋₆ alkoxy, C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and C₃₋₈ cycloalkyl), C₁₋₆ alkylsulfanyl, and C₁₋₆ alkylsulfonyl and may further be substituted by one halogen atom}; pyridyl {the pyridyl is substituted by one group selected from the group consisting of C₁₋₆ alkoxy [the C₁₋₆ alkoxy is substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], halo-C₁₋₆ alkoxy, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyl, phenoxy [the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one phenyl), and halo-C₁₋₆ alkoxy], and pyridyloxy (the pyridyloxy is optionally substituted by one C₁₋₆ alkyl) and may further be substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl}; or pyrazinyl [the pyrazinyl is substituted by one group selected from the group consisting of C₁₋₆ alkoxy (the C₁₋₆ alkoxy is substituted by one C₃₋₈ cycloalkyl) and phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl)];

(4) A particularly preferred case of R² is

phenyl [the phenyl is substituted by one group selected from the group consisting of phenoxy (the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy) and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and C₃₋₅ cycloalkyl) and may further be substituted by one halogen atom]; pyridyl {the pyridyl is substituted by one group selected from the group consisting of phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyl, phenoxy [the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one phenyl), and halo-C₁₋₆ alkoxy], and pyridyloxy (the pyridyloxy is optionally substituted by one C₁₋₆ alkyl) and may further be substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl}; or pyrazinyl substituted by one phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl).

In the above case, preferred groups in group α3 of substituents are a halogen atom, C₁₋₆ alkyl {the C₁₋₆ alkyl is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl)], phenoxy (the phenoxy is optionally substituted by one C₁₋₆ alkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl and halo-C₁₋₆ alkyl)}, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one or two halogen atoms), phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α4 of substituents), thienyl (the thienyl is optionally substituted by one C₁₋₆ alkyl), pyrazolyl (the pyrazolyl is optionally substituted by one C₁₋₆ alkyl), isoxazolyl, thiazoyl (the thiazoyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, amino, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and C₁₋₆ alkylsulfonyl), pyrimidinyl (the pyrimidinyl is optionally substituted by one amino), quinolyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, carbamoyl, C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of hydroxy, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and di-C₁₋₆ alkylamino), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), oxazolyl (the oxazolyl is optionally substituted by one or two C₁₋₆ alkyls), pyrazolyl (the pyrazolyl is optionally substituted by one or two C₁₋₆ alkyls), thiazoyl (the thiazoyl is optionally substituted by one C₁₋₆ alkyl), indazolyl (the indazolyl is optionally substituted by one C₁₋₆ alkyl), benzotriazolyl, imidazothiazoyl, and di-C₁₋₆ alkylamino], halo-C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and C₃₋₈ cycloalkyl), C₁₋₆ alkylsulfanyl, and C₁₋₆ alkylsulfonyl;

in the above case, preferred groups in group α4 of substituents are carboxy, cyano, hydroxy, sulfamoyl, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, di-C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkylsulfonyl, mono-C₁₋₆ alkylaminosulfonyl (the C₁₋₆ alkyl of the mono-C₁₋₆ alkylaminosulfonyl is optionally substituted by one hydroxy), and di-C₁₋₆ alkylaminosulfonyl;

Preferred groups in group α5 of substituents are a halogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], halo-C₁₋₆ alkoxy, phenyl (the phenyl is optionally substituted by one group selected from group α6 of substituents), pyridyl, phenoxy [the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one phenyl), and halo-C₁₋₆ alkoxy], pyridyloxy (the pyridyloxy is optionally substituted by one C₁₋₆ alkyl), and phenylsulfanyl (the phenylsulfanyl is optionally substituted by one halogen atom);

in this case, preferred groups in group α6 of substituents are a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy.

A preferred case of Y⁴ is C₁₋₃ alkanediyl, with a more preferred case of Y⁴ being methanediyl;

a preferred case of R³ is a hydrogen atom; and

a preferred case of R⁴ is —COOH.

One preferred mode of the compounds of the present invention is compounds represented by the below-mentioned formula (I-c) or pharmaceutically acceptable salts thereof:

wherein preferred modes of R¹⁵, R¹⁶, and R² are as described above.

In this case, a more preferred mode is where R² is phenyl [the phenyl is substituted by one group selected from the group consisting of phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a fluorine atom, a chlorine atom, and trifluoromethyl), C₁₋₆ alkoxy (the C₁₋₆ alkoxy is substituted by one C₃₋₈ cycloalkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one trifluoromethyl)].

Another preferred mode of the compounds of the present invention is compounds represented by the below-mentioned formula (I-a) or pharmaceutically acceptable salts thereof.

wherein preferred modes of R¹¹, R¹², R¹³, R¹⁴, and R² are as described above.

In this case, a more preferred mode is where R¹¹, R¹², R¹³, and R¹⁴ are all a hydrogen atom and where R² is C₃₋₈ cyclohexyl [the C₃₋₈ cycloalkyl is substituted by one C₁₋₆ alkyl (the C₁₋₆ alkyl is substituted by one phenyl)] or phenyl (the phenyl is substituted by one phenoxy).

Another preferred mode of the compound of the present invention is compounds represented by the below-mentioned formula (I-b) or pharmaceutically acceptable salts thereof

wherein preferred modes of R¹¹, R¹², R¹³, R¹⁴, and R² are as described above.

In this case, a more preferred mode is where R¹¹, R¹², R¹³, and R¹⁴ are all a hydrogen atom and where R² is

phenyl {the phenyl is substituted by one group selected from the group consisting of phenyl [the phenyl is optionally substituted by one to three groups which are the same or different and are selected from the group consisting of carboxy, cyano, hydroxy, sulfamoyl, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, di-C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkylsulfonyl, mono-C₁₋₆ alkylaminosulfonyl (the C₁₋₆ alkyl of the mono-C₁₋₆ alkylaminosulfonyl is optionally substituted by one hydroxy), and di-C₁₋₆ alkylaminosulfonyl], pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, amino, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and C₁₋₆ alkylsulfonyl), C₁₋₆ alkoxy [the C₁₋₆ alkoxy is substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl (the C₃₋₈cycloalkyl is optionally substituted by one C₁₋₆ alkyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of hydroxy, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and di-C₁₋₆ alkylamino), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), oxazolyl (the oxazolyl is optionally substituted by one or two C₁₋₆ alkyls), pyrazolyl (the pyrazolyl is optionally substituted by one or two C₁₋₆ alkyls), thiazoyl (the thiazoyl is optionally substituted by one C₁₋₆ alkyl), indazolyl (the indazolyl is optionally substituted by one C₁₋₆ alkyl), benzotriazolyl, imidazothiazoyl, and di-C₁₋₆ alkylamino], halo-C₁₋₆ alkoxy, C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆alkoxy), pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and C₃₋₈ cycloalkyl), C₁₋₆ alkylsulfanyl, and C₁₋₆ alkylsulfonyl, and may further be substituted by one halogen atom}; pyridyl {the pyridyl is substituted by one group selected from the group consisting of C₁₋₆ alkoxy [the C₁₋₆alkoxy is substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl) and phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], halo-C₁₋₆ alkoxy, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyl, phenoxy [the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one phenyl), and halo-C₁₋₆ alkoxy], and pyridyloxy (the pyridyloxy is optionally substituted by one C₁₋₆ alkyl) and may further be substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl}; or pyrazinyl [the pyrazinyl is substituted by one group selected from the group consisting of C₁₋₆ alkoxy (the C₁₋₆ alkoxy is substituted by one C₃₋₈ cycloalkyl) and phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl)].

In the above case, an even more preferred mode is where R¹¹, R¹², R¹³ and R¹⁴ are all a hydrogen atom and where R² is

phenyl [the phenyl is substituted by one group selected from the group consisting of phenoxy (the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy) and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and C₃₋₈ cycloalkyl) and may further be substituted by one halogen atom]; pyridyl {the pyridyl is substituted by one group selected from the group consisting of phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy). pyridyl, phenoxy [the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one phenyl), and halo-C₁₋₆ alkoxy], and pyridyloxy (the pyridyloxy is optionally substituted by one C₁₋₆ alkyl) and may further be substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl}; or pyrazinyl which is substituted by one phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl).

And other preferred modes of the compounds of the present invention are as described below (these modes also apply to the above-mentioned formulas (I-c), (I-a), and (I-b)).

One preferred case of R¹¹ is a hydrogen atom or C₁₋₄ alkyl, with a more preferred case of R¹¹ being a hydrogen atom or methyl.

One preferred case of R¹² is a hydrogen atom or C₁₋₄ alkyl, with a more preferred case of R¹² being a hydrogen atom or methyl.

Another preferred case of R¹¹ and R¹² is where the R¹¹ and R¹², together with the adjacent carbon atom, form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom, with a more preferred case of R¹¹ and R¹² being where the R¹¹ and R¹², together with the adjacent carbon atom, form C₃₋₆ cycloalkane.

One preferred case of R¹³ is a hydrogen atom, C₁₋₄ alkyl, or halo-C₁₋₄ alkyl, with a more preferred case of R¹³ being a hydrogen atom or methyl.

One preferred case of R¹⁴ is a hydrogen atom or C₁₋₄ alkyl, with a more preferred case of R¹⁴ being a hydrogen atom or methyl.

And another preferred case of R¹³ and R¹⁴ is where the R¹³ and R¹⁴, together with the adjacent carbon atom, form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom, with a more preferred case of R¹³ and R¹⁴ being where the R¹³ and R¹⁴, together with the adjacent carbon atom, form C₃₋₆ cycloalkane.

A preferred case of Y is a single bond or C₁₋₆ alkanediyl (one of the carbon atoms in the C₁₋₆ alkanediyl is optionally substituted by C₃₋₆ cycloalkane-1,1-diyl);

a more preferred case of Y is a single bond, methanediyl, ethane-1,1-diyl, propane-1,1-diyl, propane-2,2-diyl, cyclopropane-1,1-diyl, or ethane-1,2-diyl;

and an even more preferred case of Y is a single bond or methanediyl.

A preferred case of R² is C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one group selected from the group consisting of phenyl and benzyl), phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α1 of substituents), naphthyl, indanyl, tetrahydronaphthyl, pyrazolyl [the pyrazolyl is substituted by one phenyl (the phenyl is optionally substituted by one C₁₋₆ alkyl) and may further be substituted by one C₁₋₆ alkyl], imidazolyl [the imidazolyl is substituted by one phenyl], isoxazolyl [the isoxazolyl is substituted by one phenyl (the phenyl is optionally substituted by one halogen atom)], oxazolyl (the oxazolyl is substituted by one phenyl and may further be substituted by one C₁₋₆ alkyl), thiazoyl (the thiazoyl is substituted by one phenyl), pyridyl [the pyridyl is substituted by one group selected from the group consisting of phenyl, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), and phenylsulfanyl (the phenylsulfanyl is optionally substituted by one halogen atom)], pyrimidinyl (the pyrimidinyl is substituted by one group selected from the group consisting of cyclohexyl and phenyl), benzothiophenyl, quinolyl, or methylenedioxyphenyl (the methylenedioxyphenyl is optionally substituted by one or two fluorine atoms);

In this case, preferred groups in group α1 of substituents are a halogen atom, C₁₋₆ alkyl{the C₁₋₆ alkyl is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl, and C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl)]}, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α2 of substituents), thienyl, pyrazolyl (the pyrazolyl is optionally substituted by one C₁₋₆ alkyl), isoxazolyl, thiazoyl (the thiazoyl is optionally substituted by one or two C₁₋₆ alkyls), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), quinolyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl and phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], halo-C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and halo-C₁₋₆ alkyl), and C₁₋₆ alkylsulfanyl;

in this case, preferred groups in group α2 of substituents are a halogen atom, cyano, hydroxy, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, and di-C₁₋₆ alkylaminosulfonyl.

The compounds of the present invention are ones having partially saturated, nitrogen-containing heterocyclic structures and they may be in the form of their pharmaceutically acceptable salts (both types are hereinafter referred to as “compounds of the present invention” as appropriate).

Examples of the pharmaceutically acceptable salts include acid addition salts including mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; sulfonic acid salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; organic acid salts such as oxalate, tartrate, citrate, maleate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, and malate; amino acid salts such as glylcine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate; inorganic salts such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt; and salts with organic bases such as ammonium salt, triethylamine salt, diisopropylamine salt, and cyclohexylamine salt. The term “salt(s)” as used herein encompass hydrate salt(s).

The compounds of the present invention have an asymmetric center or asymmetric centers in certain cases, where they give rise to a variety of optical isomers. Therefore, the compounds of the present invention can exist as separate optical isomers (R) and (S), or as a racemate or an (RS) mixture. In the case of compounds having two or more asymmetric centers, they give rise to diastereomers due to their respective optical isomerisms. The compounds of the present invention encompass mixtures that comprise all these types of isomer in any proportions. For example, diastereomers can be separated by methods well known to those skilled in the art, say, fractional crystallization, and optically active forms can be obtained by techniques in organic chemistry that are well known for this purpose. In addition, the compounds of the present invention sometimes give rise to geometrical isomers such as cis- and trans-forms. Further in addition, the compounds of the present invention may have tautomerism to give rise to a variety of tautomers. The compounds of the present invention encompass the-above mentioned isomers, as well as mixtures comprising those isomers in any proportions.

Furthermore, if the compounds of the present invention or salts thereof form hydrates or solvates, these are also included in the scope of the compounds of the present invention or salts thereof.

The compounds of the present invention may be administered either independently or together with pharmaceutically acceptable carriers or diluents.

In order to use the compounds of the present invention as medicines, they may assume any forms, i.e., as a solid composition, a liquid composition, or other compositions, with optimum forms being chosen depending on the need. The medicines of the present invention can be produced by incorporating pharmaceutically acceptable carriers for the compounds of the present invention. Stated specifically, commonly used excipients, fillers, binders, disintegrants, coating agents, sugar coating agents, pH modifiers, solubilizers, or aqueous or non-aqueous solvents, etc. may be added and commonly used pharmaceutical formulation techniques may be applied to prepare tablets, pills, capsules, granules, dusts, powders, liquids, emulsions, suspensions, injections, etc. Examples of the excipients and fillers include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum Arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and any other substances commonly used as excipients or fillers.

In addition, the compounds of the present invention may be formulated in pharmaceutical preparations by forming inclusion compounds with α, β or γ-cyclodextrin or methylated cyclodextrin, etc.

If the compounds of the present invention are used as PHD2 inhibitors and the like, they may be administered either orally or non-orally as such. Alternatively, the compounds of the present invention may be administered either orally or non-orally as agents that comprise them as the active ingredient. Example of non-oral administration include intravenous, transnasal, percutaneous, subcutaneous, intramuscular, and sublingual administrations.

The dosage of the compounds of the present invention varies with the subject of administration, the route of administration, the disease to be treated, the symptoms, and the like; for example, if they are to be administered orally to an adult patient presenting with anemia, a single dosage typically ranges from 0.1 mg to 1000 mg, preferably from 1 mg to 200 mg and this dosage is desirably administered once to three times a day, or once every two or three days.

It should be mentioned that the compounds of the present invention have properties desirable as pharmaceutical products. A property that can be given as an example is one that enables avoiding an excessive production of erythropoietin.

The PHD2 inhibitory effect of the compounds of the present invention can be evaluated by known techniques such as the methods described herein under the Tests.

Hereinafter, the processes for producing the compounds of the present invention are described in detail but are not particularly limited to the following illustrations. In addition, the solvents to be used in reactions may be of any types that will not interfere with the respective reactions and they are not particularly limited to the following description.

On the following pages, the processes for producing the compounds represented by formula (I) or (I′)—hereinafter sometimes referred to as the compound (I) or the compound (I′)—are described.

The compound (I) or (I′) can be produced by methods known per se, for example, Processes 1 to 10 or modifications thereof. It should also be noted that in the respective production methods described below, the starting compounds may be used in the form of salts and examples of such salts include the aforementioned “pharmaceutically acceptable salts.” In addition, the target compounds may also be obtained in the form of salts and examples of such salts include the aforementioned “pharmaceutically acceptable salts.”

Further in addition, the obtained target compounds may be used in the next step in a yet-to-be purified state.

Compound (I-9) that belongs to the compound (I) or (I′) of the present invention can be produced by, for example, the following Production Process 1 or modifications thereof.

Production Process 1:

[wherein R¹¹, R¹², R¹³, R¹⁴, and R² have the same meanings as defined above; R^(a) represents a hydrogen atom, methyl, or ethyl; Y² represents a single bond or C₁₋₅ alkanediyl; P¹, P², and P³ represent common protective groups for carboxylic acids, as exemplified by the groups described in Protective Groups in Organic Synthesis (3^(rd) Edition, 1999, edited by P. G. M. Wuts and T. W. Greene), etc. and specific examples are C₁₋₆ alkyl, benzyl, 4-methoxybenzyl, 2-(trimethylsilyl)ethyl, etc.]

[Step 1-1]

This step is a process for producing compound (I-3) by performing a reductive amination reaction using compound (I-1) and compound (I-2).

Reducing agents that can be used in the reaction include sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride, borane-2-picoline complex, etc. The amount of the reducing agents to be used ranges from one to three equivalents, preferably from one to two equivalents, relative to one equivalent of compound (I-1).

Solvents that can be used in the reaction include, for example, alcoholic solvents such as methanol and ethanol; ether-based solvents such as tetrahydrofuran and dioxane; halogenated hydrocarbon-based solvents such as methylene chloride and chloroform; aromatic hydrocarbon-based solvents such as toluene and xylene; and aprotic polar solvents such as N,N-dimethyformamide.

The reaction of interest can typically be carried out at between 0° C. and the reflux temperature.

The thus obtained compound (I-3) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 1-2]

This step is a process for producing compound (I-5) by reacting compound (I-3) with compound (I-4) in the presence of a base.

Bases that can be used in the reaction typically include, for example, triethylamine, pyridine, etc. The amount of the bases to be used ranges from one to five equivalents, preferably from one to three equivalents, relative to one equivalent of compound (I-3).

Solvents that can be used in the reaction include, for example, ether-based solvents such as tetrahydrofuran and dioxane; halogenated hydrocarbon-based solvents such as methylene chloride and chloroform; aromatic hydrocarbon-based solvents such as toluene and xylene; and aprotic polar solvents such as ethyl acetate and N,N-dimethyformamide.

The reaction of interest can typically be carried out at between 0° C. and room temperature.

The thus obtained compound (I-5) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 1-3]

This step is a process for producing compound (I-6) by cyclizing compound (I-5) in the presence of a base.

Bases that can be used in the reaction typically include, for example, sodium ethoxide, sodium methoxide, sodium hydride, potassium tert-butoxide, potassium carbonate, cesium carbonate, etc. The amount of the bases to be used typically ranges from one to five equivalents, preferably from two to three equivalents, relative to one equivalent of compound (I-5).

Solvents that can be used in the reaction include, for example, alcoholic solvents such as methanol, ethanol, and propanol; ether-based solvents such as tetrahydrofuran and dioxane; halogenated hydrocarbon-based solvents such as methylene chloride and chloroform; aromatic hydrocarbon-based solvents such as toluene and xylene; and aprotic polar solvents such as ethyl acetate and N,N-dimethyformamide.

The reaction of interest can typically be carried out at between 0° C. and the reflux temperature.

The thus obtained compound (I-6) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 1-4]

This step is a process for producing compound (I-8) from compound (I-6) and compound (I-7).

Solvents that can be used in the reaction include, for example, ether-based solvents such as 1,2-dimethoxyethane, tetrahydrofuran, and dioxane; halogenated hydrocarbon-based solvents such as methylene chloride and chloroform; aromatic hydrocarbon-based solvents such as toluene and xylene; and aprotic polar solvents such as N,N-dimethyformamide.

The reaction of interest may employ a base as an additive. Examples of the base include triethylamine, N,N-diisopropylethylamine, etc.

This reaction can typically be carried out at between room temperature and the reflux temperature.

The thus obtained compound (I-8) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 1-5]

This step is a process for producing compound (I-9) by deprotecting compound (I-8).

This reaction can be carried out by, for example, the method described in Protective Groups in Organic Synthesis (3^(rd) Edition, 1999, edited by P. G. M. Wuts and T. W. Greene), etc. or modifications thereof. Specifically, if P³ is tert-butyl, 4-methoxybenzyl or trimethylsilyl, compound (I-9) can be produced using a mineral acid such as hydrochloric acid or an organic acid such as acetic acid or trifluoroacetic acid in a solvent such as an ether-based solvent, say, tetrahydrofuran or dioxane, a halogenated hydrocarbon-based solvent, say, methylene chloride or chloroform, or an aromatic hydrocarbon-based solvent, say, toluene or xylene. If P³ is benzyl or 4-methoxybenzyl, compound (I-9) can also be produced by hydrogenolysis in a solvent such as an alcoholic solvent, say, methanol or ethanol, an ether-based solvent, say, tetrahydrofman or dioxane, a halogenated hydrocarbon-based solvent, say, methylene chloride or chloroform, or an aromatic hydrocarbon-based solvent, say, toluene or xylene in the presence of a catalyst such as palladium-carbon. If P³ is 2-(trimethylsilyl)ethyl, trimethylsilyl, or tert-butyldimethylsilyl, it is also possible to produce compound (I-9) by treatment with potassium fluoride, tetrabutylammonium fluoride, etc. If P³ is methyl, ethyl, or n-propyl, the solvent to be used may be an alcoholic solvent such as methanol or ethanol, an ether-based solvent such as tetrahydrofuran or dioxane, an aromatic hydrocarbon-based solvent such as toluene or xylene, an aprotic polar solvent such as acetonitrile or N,N-dimethylformamide, water, or the like; these solvents may be used in admixture at appropriate proportions and the treatment with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, etc., can also produce compound (I-9).

The reaction of interest can typically be carried out at between room temperature and the reflux temperature.

The thus obtained compound (I-9) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

Compound (II-6) that belongs to the compound (I) or (I′) of the present invention can be produced by, for example, the following Production Process 2 or modifications thereof.

Production Process 2:

[wherein R¹¹, R¹², R¹³, R¹⁴, P¹, P², and P³ have the same meanings as defined above; R^(b) represents a hydrogen atom, phenyl, or benzyl; n represents an integer of 0 to 5].

[Step 2-1]

This step is a process for producing compound (II-2) from compound (I-1) and compound (II-1).

The reaction of interest can be carried out by a modification of the method described in Step 1-1 of Production Process 1.

The thus obtained compound (II-2) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 2-2]

This step is a process for producing compound (II-3) from compound (II-2) and compound (I-4).

The reaction of interest can be carried out by a modification of the method described in Step 1-2 of Production Process 1.

The thus obtained compound (II-3) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 2-3]

This step is a process for producing compound (II-4) from compound (II-3).

The reaction of interest can be carried out by a modification of the method described in Step 1-3 of Production Process 1.

The thus obtained compound (II-4) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 2-4]

This step is a process for producing compound (II-5) from compound (II-4) and compound (I-7).

The reaction of interest can be carried out by a modification of the method described in Step 1-4 of Production Process 1.

The thus obtained compound (II-5) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 2-5]

This step is a process for producing compound (II-6) from compound (II-5).

The reaction of interest can be carried out by a modification of the method described in Step 1-5 of Production Process 1.

The thus obtained compound (II-5) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

Compound (III-6) that belongs to the compound (I) or (I′) of the present invention can be produced by, for example, the following Production Process 3 or modifications thereof.

Production Process 3:

[wherein R¹¹, R¹², R¹³, R¹⁴, R², P¹, P², and P³ have the same meanings as defined above; L¹ represents a common leaving group, say, a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, etc.; Y³ represents C₁₋₆ alkanediyl].

[Step 3-1]

This step is a process for producing compound (III-2) by reacting compound (I-1) with compound (III-1) in the presence of a base.

Bases that can be used in the reaction include, for example, sodium hydroxide, potassium tert-butoxide, triethylamine, pyridine, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc. The amount of the bases to be used ranges from one to three equivalents relative to one equivalent of compound (I-1).

Solvents that can be used in the reaction include, for example, alcoholic solvents such as methanol and ethanol; ether-based solvents such as tetrahydrofuran and dioxane; halogenated hydrocarbon-based solvents such as methylene chloride and chloroform; aromatic hydrocarbon-based solvents such as toluene and xylene; and aprotic polar solvents such as acetonitrile and N,N-dimethyformamide.

The reaction of interest can typically be carried out at between 0° C. and the reflux temperature.

The thus obtained compound (III-2) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 3-2]

This step is a process for producing compound (III-3) from compound (III-2) and compound (I-4).

The reaction of interest can be carried out by a modification of the method described in Step 1-2 of Production Process 1.

The thus obtained compound (III-3) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 3-3]

This step is a process for producing compound (III-4) from compound (III-3).

The reaction of interest can be carried out by a modification of the method described in Step 1-3 of Production Process 1.

The thus obtained compound (III-4) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 3-4]

This step is a process for producing compound (III-5) from compound (III-4) and compound (I-7).

The reaction of interest can be carried out by a modification of the method described in Step 1-4 of Production Process 1.

The thus obtained compound (III-5) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 3-5]

This step is a process for producing compound (III-6) from compound (III-5).

The reaction of interest can be carried out by a modification of the method described in Step 1-5 of Production Process 1.

The thus obtained compound (III-6) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

Compound (IV-7) that belongs to the compound (I) or (I′) of the present invention can be produced by, for example, the following Production Process 4 or modifications thereof.

Production Process 4:

[wherein R¹¹, R¹³, R¹⁴, R², P¹, P², and P³ have the same meanings as defined above; Y¹ represents a single bond or C₁₋₆ alkanediyl (one of the carbon atoms in the C₁₋₆ alkanediyl is optionally substituted by C₃₋₆ cycloalkane-1,1-diyl)].

[Step 4-1]

This step is a process for producing compound (IV-3) by reacting compound (IV-1) with compound (IV-2).

Solvents that can be used in the reaction include alcoholic solvents such as methanol and ethanol; ether-based solvents such as tetrahydrofuran and dioxane; halogenated hydrocarbon-based solvents such as methylene chloride and chloroform; aromatic hydrocarbon-based solvents such as toluene and xylene; aprotic polar solvents such as acetonitrile and N,N-dimethyformamide; water, etc; these solvents may be used in admixture at appropriate proportions.

In the reaction of interest, a base or an acid may be used as an additive. Examples of the base include sodium hydride, potassium tert-butoxide, triethylamine, pyridine, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc. Examples of the acid include acetic acid, hydrochloric acid, sulfuric acid, etc.

The reaction of interest can typically be carried out at between 0° C. and the reflux temperature; it may even be carried out under irradiation with microwaves.

The thus obtained compound (IV-3) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 4-2]

This step is a process for producing compound (IV-4) from compound (IV-3) and compound (I-4).

The reaction of interest may be carried out by a modification of the method described in Step 1-2 of Production Process 1.

The thus obtained compound (IV-4) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 4-3]

This step is a process for producing compound (IV-5) from compound (IV-4).

The reaction of interest may be carried out by a modification of the method described in Step 1-3 of Production Process 1.

The thus obtained compound (IV-5) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 4-4]

This step is a process for producing compound (IV-6) from compound (IV-5) and compound (I-7).

The reaction of interest may be carried out by a modification of the method described in Step 1-4 of Production Process 1.

The thus obtained compound (IV-6) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 4-5]

This step is a process for producing compound (IV-7) from compound (IV-6).

The reaction of interest may be carried out by a modification of the method described in Step 1-5 of Production Process 1.

The thus obtained compound (IV-7) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

Compound (V-4) that belongs to the compound (I) or (I′) of the present invention can be produced by, for example, the following Production Process 5 or modifications thereof.

Production Process 5:

[wherein R¹¹, R¹², R¹³, R¹⁴, Y¹ and P³ have the same meanings as defined above; ring A represents phenyl (the phenyl is optionally substituted by one to four groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and C₃₋₈ cycloalkoxy) or pyridyl (the pyridyl is optionally substituted by one to three groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy); L² represents a common leaving group, say, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, trifluoromethanesulfonyloxy, etc.; M¹-R^(c) represents a metal-containing organometallic compound, wherein M¹ represents boronic acid, a boronic acid ester, magnesium bromide, magnesium chloride, etc. and R^(c) represents C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α2 of substituents), thienyl, pyrazolyl (the pyrazolyl is optionally substituted by one C₁₋₆ alkyl), isoxazolyl, thiazoyl (the thiazoyl is optionally substituted by one or two C₁₋₆ alkyls), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl, halo-C₁₋₆ alkyl. C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), quinolyl, etc.; compound (V-1) can be produced by implementing the procedures of the steps in Production Processes 1 to 4].

[Step 5-1]

This step is a process for producing compound (V-3) by performing a coupling reaction using compound (V-1) and organometallic compound (V-2).

If M¹ is boronic acid or a boronic acid ester, the reaction of interest is the so-called Suzuki-Miyaura coupling reaction and can be carried out by documented processes (Tetrahedron Letters, 1979, 20, 3437-3440; Chemical reviews, 1995, 95, 2457-2483) or modifications thereof in the presence of a palladium catalyst and a base. If M¹ is a Grignard reagent such as magnesium bromide or magnesium chloride, compound (V-3) can be produced in the presence of a palladium catalyst.

In this case, a metallic reagent such as indium chloride may be added as appropriate. The amount of compound (V-2) to be used in the step under consideration ranges from one to five equivalents, preferably from one to three equivalents, relative to one equivalent of compound (V-1).

Palladium catalysts that may be used in the coupling reaction include those which are known to skilled artisans, as exemplified by tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, bis(triphenylphosphine)palladium(II) acetate and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (1:1), etc. If desired, a palladium(0) catalyst, as generated in the system using palladium(II) acetate and a phosphine reagent such as triphenylphosphine or tri(2-methylphenyl)phosphine in the presence of a base, may be used for the reaction. The amount of the palladium catalyst to be used typically varies from 0.01 to 0.5 equivalents, preferably from 0.05 to 0.3 equivalents, relative to one equivalent of compound (V-1).

Bases that can be used include potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, tripotassium phosphate, potassium fluoride, cesium fluoride, triethylamine, etc. The amount of the bases to be used typically varies from one to five equivalents, preferably from one to three equivalents, relative to one equivalent of compound (V-1).

Solvents that can be used in the reaction include alcoholic solvents such as methanol, ethanol, and ethylene glycol; ether-based solvents such as tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; aromatic hydrocarbon-based solvents such as toluene and xylene; aprotic polar solvents such as acetonitrile and N,N-dimethyformamide; water, etc; these solvents may be used in admixture at appropriate proportions.

In the reaction of interest, a copper compound may be used as an additive. Examples of the copper compound include copper(I) iodide, copper(II) acetate, etc.

The reaction of interest can typically be carried out at between room temperature and 180° C.; it may even be carried out under irradiation with microwaves.

The thus obtained compound (V-3) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 5-2]

This step is a process for producing compound (V-4) from compound (V-3).

The reaction of interest can be carried out by a modification of the method described in Step 1-5 of Production Process 1.

The thus obtained compound (V-4) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

Compound (VI-2) that belongs to the compound (I) or (I′) of the present invention can be produced by, for example, the following Production Process 6 or modifications thereof

Production Process 6:

[wherein R¹¹, R¹², R¹³, R¹⁴, Y¹, ring A, L², M¹, and R^(c) have the same meanings as defined above, and compound (VI-1) can be produced by implementing the procedures of the steps in Production Processes 1 to 4].

[Step 6-1]

This step is a process for producing compound (VI-2) from compound (VI-1) and organometallic compound (V-2).

The reaction of interest can be carried out by a modification of the method described in Step 5-1 of Production Process 5.

The thus obtained compound (VI-2) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

Compound (VII-6) that belongs to the compound (I′) of the present invention can be produced by, for example, the following Production Process 7 or modifications thereof.

Production Process 7:

[wherein R¹⁵, R¹⁶, R^(a), R², Y², P¹, P², and P³ have the same meanings as defined above].

[Step 7-1]

This step is a process for producing compound (VII-2) from compound (VII-1) and compound (I-2).

The reaction of interest can be carried out by a modification of the method described in Step 1-1 of Production Process 1.

The thus obtained compound (VII-2) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 7-2]

This step is a process for producing compound (VII-3) from compound (VII-2) and compound (I-4).

The reaction of interest can be carried out by a modification of the method described in Step 1-2 of Production Process 1.

The thus obtained compound (VII-3) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 7-3]

This step is a process for producing compound (VII-4) from compound (VII-3).

The reaction of interest can be carried out by a modification of the method described in Step 1-3 of Production Process 1.

The thus obtained compound (VII-4) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 7-4]

This step is a process for producing compound (VII-5) from compound (VII-4) and compound (I-7).

The reaction of interest can be carried out by a modification of the method described in Step 1-4 of Production Process 1.

The thus obtained compound (VII-5) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 7-5]

This step is a process for producing compound (VII-6) from compound (VII-5).

The reaction of interest can be carried out by a modification of the method described in Step 1-5 of Production Process 1.

The thus obtained compound (VII-6) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

Compound (VIII-4) that belongs to the compound (I′) of the present invention can be produced by, for example, the following Production Process 8 or modifications thereof.

Production Process 8:

[wherein R¹⁵, R¹⁶, R^(a), R², Y², P¹, and P³ have the same meanings as defined above].

[Step 8-1]

This step is a process for producing compound (VIII-2) by performing a condensation reaction using compound (VII-2) and compound (VIII-1).

Reagents that can be used in the condensation reaction include the combination of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole, as well as 1,1′-carbonyldiimidazole, propylphosphonic acid anhydride (cyclic trimer), etc. The amount of the condensation agent to be used varies from one to three equivalents, preferably from one to two equivalents, relative to one equivalent of compound (VII-2).

In the reaction of interest, a base can be used as an additive. Examples of the base include triethylamine and so forth.

Solvents that can be used in the reaction include, for example, alcoholic solvents such as methanol and ethanol; ether-based solvents such as tetrahydrofuran and dioxane; halogenated hydrocarbon-based solvents such as methylene chloride and chloroform; aromatic hydrocarbon-based solvents such as toluene and xylene; and aprotic polar solvents such as N,N-dimethylformamide.

The reaction of interest can typically be carried out at between 0° C. and the reflux temperature.

The thus obtained compound (VIII-2) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 8-2]

This step is a process for producing compound (VIII-3) from compound (VIII-2). The reaction of interest can be carried out by a modification of the method described in Step 1-3 of Production Process 1.

The thus obtained compound (VIII-3) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 8-3]

This step is a process for producing compound (VIII-4) from compound (VIII-3). The reaction of interest can be carried out by a modification of the method described in Step 1-5 of Production Process 1.

The thus obtained compound (VIII-4) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

Compound (IX-4) that belongs to the compound (I) or (I′) of the present invention can be produced by, for example, the following Production Process 9 or modifications thereof.

Production Process 9:

[wherein R¹¹, R¹², R¹³, R¹⁴, R², Y¹, P¹, and P³ have the same meanings as defined above, and compound (IX-1) can be produced by implementing the procedures of Production Processes 1 to 4].

[Step 9-1]

This step is a process for producing compound (IX-2) by performing a condensation reaction using compound (IX-1) and compound (VIII-1).

The reaction of interest can be carried out by a modification of the method described in Step 8-1 of Production Process 8.

The thus obtained compound (IX-2) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 9-2]

This step is a process for producing compound (IX-3) from compound (IX-2).

The reaction of interest can be carried out by a modification of the method described in Step 1-3 of Production Process 1.

The thus obtained compound (IX-3) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 9-3]

This step is a process for producing compound (IX-4) from compound (IX-3).

The reaction of interest can be carried out by a modification of the method described in Step 1-5 of Production Process 1.

The thus obtained compound (IX-4) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

Compound (X-4) that belongs to the compound (I′) of the present invention can be produced by, for example, the following Production Process 10 or modifications thereof.

Production Process 10:

[wherein R¹¹, R¹², R¹³, R¹⁴, R², R³, Y¹, Y⁴, P², and P³ have the same meanings as defined above, and compound (X-1) can be produced by implementing the procedures of Production Processes 1 to 4].

[Step 10-1]

This step is a process for producing compound (X-3) from compound (X-1) and compound (X-2).

The reaction of interest can be carried out by a modification of the method described in Step 1-4 of Production Process 0.1.

The thus obtained compound (X-3) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

[Step 10-2]

This step is a process for producing compound (X-4) from compound (X-3).

The reaction of interest can be carried out by a modification of the method described in Step 1-5 of Production Process 1.

The thus obtained compound (X-4) can be isolated and purified by known separation/purification means, such as concentrating, concentrating under reduced pressure, re-precipitation, extraction with solvent, crystallization, chromatography, etc.

EXAMPLES

The present invention is described in greater detail by means of the following Reference Examples, Working Examples, and Tests but it should be understood that these are by no means intended to limit the present invention and may be changed to the extent that will not depart from the scope of the present invention.

The abbreviations used herein denote the following meanings.

s: singlet d: doublet t: triplet q: quartet quin: quintet sept: septet dd: double doublet dt: double triplet td: triplet doublet m: multiplet br: broad J: coupling constant

Hz: Hertz

CHLOROFORM-d: deuterated chloroform DMSO-d₆: deuterated dimethyl sulfoxide METHANOL-d₄: deuterated methanol

Proton nuclear magnetic resonance (¹H-NMR) spectrometry was implemented by the following Fourier transform NMR spectrometers.

200 MHz: Gemini 2000 (Agilent Technologies) 300 MHz: Inova 300 (Agilent Technologies) 600 MHz: JNM-ECA 600 (JEOL)

For analysis, ACD/SpecManager ver. 12.01 (product name), ACD/Spectrus Processor™, etc. were used. Very mild peaks derived from the protons of a hydroxy group, an amino group and other species are not reported.

Mass spectrometry (MS) was implemented by the following spectrometers.

Platform LC (Waters) LCMS-2010EV (Shimadzu) LCMS-IT-TOF (Shimadzu) GCT (Micromass) Agilent 6130 (Agilent) LCQ Deca XP (ThermoFisher Scientific)

The ionization technique used was ESI (electrospray ionization), EI (electron ionization), or dual ionization employing ESI and APCI (atmospheric pressure chemical ionization). Found data are reported. Molecular ion peaks are usually observed but in the case of compounds having a hydroxy group (—OH), fragment peaks are sometimes observed with H₂O eliminated. In the case of salts, molecular ion peaks or fragment ion peaks of their free forms are usually observed.

Purification by preparative high-performance liquid chromatography (preparative HPLC) was conducted under the following conditions. It should, however, be noted that in the case of compounds having basic functional groups, neutralization or other operations for obtaining their free forms may have to be performed when trifluoroacetic acid is used in the HPLC operation.

Apparatus: Gilson's preparative HPLC system

Column: Waters' SunFire™ Prep C18 OBD™ (5 μm, 30×50 mm)

Flow rate: 40 mL/min; Detection method: UV 254 nm Solvent: Solution A, 0.1% trifluoroacetic acid containing water; Solution B, 0.1% trifluoroacetic acid containing acetonitrile

Gradient: 0 min (Solution A/Solution B=90/10), 2 min (Solution A/Solution B=90/10), 12 min (Solution A/Solution B=20/80), 13.5 min (Solution A/Solution B=5/95), 15 min (Solution A/Solution B=5/95)

Analysis by optical high-performance liquid chromatography (optical HPLC) was conducted under the following conditions.

Apparatus: Agilent 1100 (product of Agilent)

Column: DAICEL's CHIRALCEL OD-H (5 μm, 4.6×250 mm)

Flow rate: 0.5 mL/min; Detection method: UV 254 nm Solvent: 0.1% trifluoroacetic acid containing acetonitrile

Purification by optical preparative high-performance liquid chromatography (optical preparative HPLC) was conducted under the following conditions.

Apparatus: Gilson's preparative HPLC system

Column: DAICEL's CHIRALCEL OD (10 μm, 20×250 mm)

Flow rate: 5 mL/min; Detection method: UV 254 nm Solvent: 0.1% trifluoroacetic acid containing acetonitrile

For X-ray crystallography, XR-AXIS RAPID II (Rigaku) was used.

The optical purity of optically active forms was evaluated in terms of percent enantiomeric excess (% ee). This parameter was calculated from the following equation using the data obtained by optical HPLC.

{For (R)-form}

Percent enantiomeric excess(% ee)=100×[(R)−(S)]/[(R)+(S)]

[wherein (R) and (S) represent the absolute configurations of the respective enantiomers, as well as their peak areas in optical high-performance liquid chromatography (HPLC)].

Percent enantiomeric excess was similarly determined for the (S)-form.

The phase separator used was Biotage's ISOLUTE (registered trademark) Phase Separator.

The microwave reactor was Biotage's Initiator.

Compound names were assigned by means of ACD/Name (ACD/Labs 12.01, Advanced Chemistry Development Inc.)

Elemental analysis was conducted with the following apparatuses.

240011 (Perkin Elmer)

vario MICRO cube (elementar)

MT-6 (Yanaco Analytical Instruments Inc.)

Ion chromatographic analysis was conducted with the following apparatuses.

DX500 (Dionex) XS 100 (Mitsubishi Chemical Corporation) ICS3000 (Dionex)

Melting points were measured with the following apparatus.

MP-J3 (Yanaco Instrument Development Laboratory)

In the tables given in the Reference Examples and Working Examples, salt information is left blank for some compounds, indicating that they were obtained in the form of free forms.

Reference Example 1-1 Methyl (4-aminotetrahydro-2H-pyran-4-yl)acetate hydrochloride

(1) Synthesis of methyl tetrahydro-4H-pyran-4-ylidene acetate

To a solution of tetrahydro-4H-pyran-4-one (10.0 g) in toluene (200 mL), methyl (triphenylphosphoranylidene)acetate was added at room temperature. After stirring at 100° C. for 15 hours, the mixture was cooled to room temperature. After concentrating under reduced pressure, ethyl acetate (200 mL) and n-hexane (200 mL) were added. After removing the precipitate by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-50:50) to give methyl tetrahydro-4H-pyran-4-ylidene acetate as a colorless oil (13.9 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.30-2.37 (m, 2H) 2.95-3.05 (m, 2H) 3.70 (s, 3H) 3.71-3.81 (m, 4H) 5.69 (s, 1H).

MS ESI/APCI Dual posi: 157 [M+H]⁺, 179 [M+Na]⁺.

(2) Synthesis of methyl (4-aminotetrahydro-2H-pyran-4-yl)acetate

An 8 mol/L ammonia-methanol solution (100 mL) of the compound (13.6 g) obtained in step (1) above was stirred in a sealed tube at 90° C. for 4 days. After being cooled to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to give methyl (4-aminotetrahydro-2H-pyran-4-yl)acetate as a yellow oil (7.09 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44-1.56 (m, 2H) 1.64-1.79 (m, 2H) 2.45 (s, 2H) 3.63-3.86 (m, 7H).

MS ESI/APCI Dual posi: 174 [M+H]⁺, 196 [M+Na]⁺.

(3) Synthesis of the Titled Compound

To an ethyl acetate solution (100 mL) of the compound (7.09 g) in step (2) above, a 4 mol/L hydrogen chloride-ethyl acetate solution (10.2 mL) was added. Thereafter, n-hexane was added and the mixture was stirred at room temperature for 5 minutes. The precipitate was recovered by filtration to give the titled compound as a colorless solid (5.72 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.76-1.85 (m, 4H) 2.90 (s, 2H) 3.49-3.61 (m, 2H) 3.63-3.68 (m, 3H) 3.70-3.83 (m, 2H) 8.35 (br. s., 3H).

MS ESI/APCI Dual posi: 174 [M+H]⁺.

Reference Example 1-2 tert-Butyl 4-amino-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate

Instead of tetrahydro-4H-pyran-4-one, 1-(tert-butoxycarbonyl)-4-piperidone (5.00 g) was used and treated by the same techniques as in Reference Example 1-1(1) and (2) to give the titled compound as a colorless solid (4.65 g).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 1.49-1.52 (m, 2H) 1.53-1.60 (m, 2H) 2.41 (s, 2H) 3.28-3.35 (m, 2H) 3.58-3.68 (m, 2H) 3.69 (s, 3H).

MS ESI/APCI Dual posi: 273 [M+H]⁺.

Reference Example 1-3 tert-Butyl 3-amino-3-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate

(1) Synthesis of tert-butyl 3-(2-methoxy-2-oxoethylidene)azetidine-1-carboxylate

Instead of tetrahydro-4H-pyran-4-one, 1-(tert-butoxycarbonyl)-4-azetidinone (4.90 g) was used and treated by the same technique as in Reference Example 1-1(1) to give tert-butyl 3-(2-methoxy-2-oxoethylidene)azetidine-1-carboxylate as a colorless oil (6.21 g).

¹H NMR (200 MHz, DMSO-d₆) δ ppm 1.38-1.41 (m, 9H) 3.61-3.67 (m, 3H) 4.52-4.60 (m, 2H) 4.66-4.73 (m, 2H) 5.84-5.93 (m, 1H) MS ESI/APCI Dual nega: 226 [M−H]⁻.

(2) Synthesis of the Titled Compound

To a solution in ethanol (60 mL) of the compound (6.04 g) obtained in step (1) above, a solution of 28% ammonia in water was added and the mixture was stirred at 80° C. for 9 hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give the titled compound as a crude product (8.14 g). The titled compound was used in the next reaction as it remained the crude product.

Reference Example 2-1 Methyl (1-aminocyclobutyl)acetate

(1) Synthesis of 1-azaspiro[3.3]heptan-2-one

To a solution of methylenecyclobutane (2.35 g) in diethyl ether (34.9 mL), chlorosulfonyl isocyanate (4.88 g) was slowly added under cooling with ice and the mixture was stirred at room temperature for 30 minutes. After successively adding a solution of 20% sodium thiosulfate in water (43.0 mL) and a solution of 10% potassium hydroxide in water (43.0 mL) at 0° C., the mixture was stirred at that temperature for 2 hours. Following the confirmation that the interior of the reaction system was strongly basic, the mixture was extracted with diethyl ether nine times. The combined organic layers were dried over anhydrous magnesium sulfate and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give 1-azaspiro[3.3]heptan-2-one as a yellow oil (2.71 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.63-1.82 (m, 2H) 2.17-2.45 (m, 4H) 2.96-2.99 (m, 2H) 5.90-6.56 (m, 1H).

MS ESI posi: 112 [M+H]⁺, 134 [M+Na]⁺.

(2) Synthesis of the Titled Compound

To a solution in methanol (60.0 mL) of the compound (2.67 g) obtained in step (1) above, cone. sulfuric acid was added slowly. After refluxing for an hour, the mixture was cooled to room temperature. After concentrating the mixture under reduced pressure, ethyl acetate was added and the mixture was extracted with 1 mol/L hydrochloric acid twice. To the combined aqueous layers, potassium carbonate was added at 0° C. until pH>10. After ten extractions with ethyl acetate, the combined organic layers were dried over added anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give the titled compound as a pale yellow oil (2.82 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.59-1.99 (m, 4H) 2.03-2.16 (m, 2H) 2.61 (s, 2H) 3.69 (s, 3H).

MS ESI posi: 144 [M+H]⁺, 166 [M+Na]⁺.

Reference Example 2-2 Methyl 3-amino-2,2,3-trimethylbutanoate hydrochloride

(1) Synthesis of 3,3,4,4-tetramethylazetidine-2-one

To a solution of 2,3-dimethyl-2-butene (5.76 g) in toluene (46.0 mL), chlorosulfonyl isocyanate (5.91 mL) was added at 0° C. After being stirred at that temperature for 10 minutes, the mixture was brought to room temperature. After being stirred for 45 minutes, the mixture was diluted with added toluene (69.0 mL). To a mixture of a solution of 25% sodium hydroxide in water (49.1 mL) and benzyltriethylammonium chloride (99.0 mg), the reaction mixture was added over a period of one hour. The resulting mixture was added dropwise to a solution of 25% sodium hydroxide in water and the mixture was stirred at 50° C. for an hour. After being cooled to room temperature, the mixture was extracted with toluene twice. The combined organic layers were washed with saturated brine and dried over added anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized with toluene to give 3,3,4,4-tetramethylazetidine-2-one as a colorless solid (5.52 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (s, 6H) 1.33 (s, 6H) 5.79 (br. s, 1H).

MS ESI/APCI Dual posi: 128 [M+H]⁺, 150 [M+Na]⁺.

MS ESI/APCI Dual nega: 126 [M−H]⁻.

(2) Synthesis of the Titled Compound

To the compound (5.52 g) obtained in step (1) above, a 2 mol/L hydrogen chloride-methanol solution (40.0 mL) was added and the mixture was refluxed for 5 hours. Further, a 2 mol/L hydrogen chloride-methanol solution (20.0 mL) was added and the mixture was refluxed for 6 hours. After cooling to room temperature, toluene (40.0 mL) was added and the mixture was concentrated under reduced pressure. After cooling the residue to 0° C., the precipitate was recovered by filtration and washed with toluene. The recovered precipitate was dried under reduced pressure to give the titled compound as a colorless solid (4.67 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 6H) 1.51 (s, 6H) 3.73-3.83 (m, 3H) 8.25-8.83 (m, 3H).

MS ESI/APCI Dual posi: 160 [M+H]⁺, 182 [M+Na]⁺.

Reference Example 2-3 Methyl 3-amino3-ethylpentanoate hydrochloride

Instead of 2,3-dimethyl-2-butene, 2-ethyl-1-butene (10.0 g) was used and treated by the same technique as in Reference Example 2-2 to give the titled compound as a colorless amorphous mass (12.0 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06 (t, J=7.5 Hz, 6H) 1.79-2.02 (m, 4H) 2.80 (s, 2H) 3.74 (s, 3H) 8.52 (br. s., 3H).

MS ESI/APCI Dual posi: 160 [M+H]⁺, 182 [M+Na]⁺.

Reference Example 3-1 Ethyl 3-amino-2,2-difluoropropanoate hydrochloride

To ethanol (12.0 mL), thionyl chloride (0.587 mL) was added at 0° C. and the mixture was stirred at that temperature for 30 minutes. After adding 3-amino-2,2-difluoropropionic acid hydrochloride (950 mg) at 0° C., the mixture was refluxed for 4 hours. After being cooled to room temperature, the mixture was concentrated under reduced pressure. After adding ethyl acetate, the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to give the titled compound as a pale brown oil (920 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=7.0 Hz, 3H) 3.84 (t, J=14.1 Hz, 2H) 4.40 (q, J=7.0 Hz, 2H) 8.70 (br. s., 3H).

MS ESI/APCI Dual posi: 154 [M+H]⁺.

In the following Reference Examples 3-2 and 3-3, a commercial grade of the corresponding β-alanine compounds was used as the starting material and treated by the method described in Reference Example 3-1 or a modification thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 1-1 below.

TABLE 1-1 Compound No. Structure Analytical Data Salt information Reference Example 3-2

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.28 (m, 3 H) 2.65-2.92 (m, 2 H) 2.96-3.11 (m, 1 H) 3.40-3.53 (m, 1 H) 3.74-3.91 (m, 1 H) 4.09-4.20 (m, 2 H) 7.21-7.38 (m, 5 H) 8.54-8.88 (m, 3 H). MS ESI/APCI Dual posi: 208[M + H]⁺, 230[M + Na]⁺. HCl Reference Example 3-3

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (t, J = 7.1 Hz, 3 H) 1.94-2.42 (m, 2 H) 2.66-2.99 (m, 4 H) 3.51-3.74 (m, 1 H) 4.09-4.20 (m, 2 H) 7.14-7.30 (m, 5 H) 8.66 (br. s., 3 H). MS ESI/APCI Dual posi: 222[M + H]⁺, 244[M + Na]⁺. HCl

Reference Example 3-4 Methyl (3R)-3-amino-4-hydroxybutanoate hydrochloride

To a solution of L-β-homoserine (1.00 g) in methanol (8.4 mL), a 4 mol/L hydrogen chloride-1,4-dioxane solution (8.4 mL) was added and thereafter the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give the titled compound as a pale yellow oil (1.42 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.69 (d, J=6.5 Hz, 2H) 3.34-3.60 (m, 2H) 3.64 (s, 3H) 4.27-4.57 (m, 1H).

MS ESI/APCI Dual posi: 134 [M+H]⁺.

Reference Example 3-5 Methyl (3S)-3-amino-4-hydroxybutanoate hydrochloride

Instead of L-β-homoserine, D-β-homoserine (1.00 g) was used and treated by the same technique as in Reference Example 3-4 to give the titled compound as a pale yellow oil (1.42 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.70 (d, J=6.7 Hz, 2H) 3.35-3.60 (m, 2H) 3.64 (s, 3H) 4.29-4.55 (m, 1H).

MS ESI/APCI Dual posi: 134 [M+H]⁺.

Reference Example 4-1 Ethyl (1-amino cyclopropyl)acetate hydrochloride

(1) Synthesis of 3-(benzyloxy)propanenitrile

To a suspension of sodium hydride (60% dispersion in mineral oil; 14.6 g) in tetrahydrofuran (281 mL), ethylene cyanohydrin (21.0 mL) was added dropwise at 0° C. and the mixture was stirred at that temperature for 40 minutes. After adding benzyl bromide (44.4 mL) to the reaction mixture, the resulting mixture was stirred overnight as it was brought to room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate three times. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=100:0-70:30) to give 3-(benzyloxy)propanenitrile as a colorless oil (24.7 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.63 (t, J=6.4 Hz, 2H) 3.69 (t, J=6.4 Hz, 2H) 4.59 (s, 2H) 7.27-7.41 (m, 5H).

(2) Synthesis of 1-[2-(benzyloxy)ethyl]cyclopropaneamine

To a mixture of the compound (24.7 g) obtained in step (1) above, tetraisopropyl orthotitanate (49.4 mL) and methoxycyclopentane (306 mL), ethyl magnesium bromide (about 3 mol/L, solution in diethyl ether, 102 mL) was added at 0° C. and thereafter the mixture was stirred at room temperature for 3 hours. After adding boron trifluoride/diethylether complex (38.8 mL) at 0° C., the mixture was stirred at room temperature for 1.5 hours. After adding water at 0° C., pH was adjusted to 12 by adding a solution of 10% sodium hydroxide in water. The reaction mixture was extracted with chloroform three times. The combined organic layers were washed with saturated brine and then passed through a phase separator and concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=100:0-5:95) and further purified by silica gel column chromatography (n-hexane:ethylacetate=90:10-5:95, then chloroform:methanol=100:0-90:10) to give 1-[2-(benzyloxy)ethyl]cyclopropaneamine as a pale yellow oil (12.5 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.40-0.45 (m, 2H) 0.53-0.59 (m, 2H) 1.73 (t, J=6.4 Hz, 2H) 3.69 (t, J=6.4 Hz, 2H) 4.52-4.55 (m, 2H) 7.27-7.37 (m, 5H).

(3) Synthesis of tert-butyl {1-[2-(benzyloxy)ethyl]cyclopropyl}carbamate

To a solution in tetrahydrofuran (130 mL) of the compound (12.5 g) obtained in step (2) above, an aqueous solution of sodium hydrogencarbonate (7.8%, 106 g) and di-tert-butyl dicarbonate (22.5 mL) were added successively and the mixture was stirred at room temperature for 14 hours. After adding saturated brine, the mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated brine and then passed through a phase separator and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) to give tert-butyl {1-[2-(benzyloxy)ethyl]cyclopropyl}carbamate as a colorless solid (16.3 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.61-0.80 (m, 4H) 1.41 (s, 9H) 1.84 (t, J=6.3 Hz, 2H) 3.63 (t, J=6.3 Hz, 2H) 4.51 (s, 2H) 4.88 (br. s, 1H) 7.27-7.39 (m, 5H).

(4) Synthesis of tert-butyl[1-(2-hydroxyethyl)cyclopropyl]carbamate

To a solution in ethanol (112 mL) of the compound (16.3 g) obtained in step (3) above, 20% palladium hydroxide/carbon (3.25 g) was added and the mixture was stirred at 60° C. for 23 hours in a hydrogen atmosphere. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give tert-butyl[1-(2-hydroxyethyl)cyclopropyl]carbamate as a colorless solid (11.1 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.71-0.78 (m, 2H) 0.79-0.87 (m, 2H) 1.44 (s, 9H) 1.60-1.66 (m, 2H) 3.65-3.78 (m, 2H) 4.83-4.99 (m, 1H).

(5) Synthesis of {1-[(tert-butoxycarbonyl)amino]cyclopropyl}acetic acid

To a solution in acetonitrile (275 mL) of the compound (11.1 g) obtained in step (4) above and 2,2,6,6-tetramethylpiperidin-1-oxyl free radical (602 mg), a sodium phosphate buffer (0.67 mol/L, pH 6.7, 206 mL) was added. After heating to 35° C., an aqueous solution of sodium hypochlorite (0.265%, 32.6 mL) and an aqueous solution of sodium chlorite (14.7%, 110 mL) were added simultaneously over a period of 2 hours and the mixture was stirred at that temperature for 55 hours. The mixture was cooled to room temperature and after adding water (400 mL), it was rendered basic with a solution of 2 mol/L sodium hydroxide in water. The reaction mixture was poured into an aqueous solution of sodium thiosulfate (5.75%, 291 mL) at 0° C. After washing with diethyl ether (750 mL), the aqueous layer was added to 2 mol/L hydrochloric acid (140 mL) for pH adjustment to between 2 and 3. The mixture was extracted with diethyl ether and ethyl acetate and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was crystallized with a liquid mixture of n-hexane/ethyl acetate to give {1-[(tert-butoxycarbonyl)amino]cyclopropyl}acetic acid as a colorless solid (9.45 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.73-0.83 (m, 2H) 0.89-0.96 (m, 2H) 1.45 (s, 9H) 2.41-2.82 (m, 2H) 5.09-5.49 (m, 1H).

MS ESI/APCI Dual posi: 238 [M+Na]⁺.

MS ESI/APCI Dual nega: 214 [M−H]⁻.

(6) Synthesis of the Titled Compound

To ethanol (34.8 mL), thionyl chloride (1.51 mL) was added at 0° C. and the mixture was stirred at that temperature for 30 minutes. After adding the compound (1.50 g) obtained in step (5) above, the mixture was stirred at 75° C. for 4 hours. After being cooled to room temperature, the mixture was concentrated under reduced pressure to give the titled compound as a pale yellow oil (1.41 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.73-0.81 (m, 2H) 1.30 (t, J=7.2 Hz, 3H) 1.44-1.51 (m, 2H) 2.74 (s, 2H) 4.23 (q, J=7.2 Hz, 2H).

MS ESI/APCI Dual posi: 144 [M+H]⁺.

Reference Example 5-1 Ethyl 1-(aminomethyl)cyclopropanecarboxylate

(1) Synthesis of ethyl 1-cyanocyclopropanecarboxylate

To a solution of ethyl cyanoacetate (11.8 g) in acetone (83.0 mL), potassium carbonate (43.1 g) and 1,2-dibromoethane (39.2 g) were added and the mixture was refluxed for 12 hours. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure and further dried under reduced pressure with heating to give ethyl 1-cyanocyclopropanecarboxylate as a red oil (14.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.23 (t, J=7.1 Hz, 3H) 1.57-1.62 (m, 2H) 1.73-1.79 (m, 2H) 4.19 (q, J=7.1 Hz, 2H).

(2) Synthesis of the Titled Compound

To a solution in ethanol (127 mL) of the compound (14.0 g) obtained in step (1) above, a Raney nickel catalyst (about 2.8 g) was added. In a hydrogen atmosphere, the mixture was stirred at room temperature for 12 hours and further stirred at 40° C. for 12 hours. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. The resulting precipitate was recovered by filtration and washed with ethanol. The filtrate was concentrated to give the titled compound as a red oil (13.4 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.82-0.88 (m, 2H) 0.98-1.04 (m, 2H) 1.13-1.21 (m, 3H) 2.63-2.72 (m, 2H) 4.00-4.10 (m, 2H).

In the following Reference Examples 5-2 to 5-5, 1,2-dibromoethane was replaced by a commercial grade of the corresponding dihalogenated alkanes or dihalogenated alkyl ethers, which were treated by the method described in. Reference Example 5-1 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 2-1 below.

TABLE 2-1 Compound No. Structure Analytical Data Salt information Reference Example 5-2

¹H HMR (300 Mz, CHLOROFORM-d) δ ppm 1.22-1.31 (t, J = 7.0 Hz, 3 H) 1.46-2.39 (m, 8 H) 2.81 (s, 2 H) 4.16 (q, J = 7.0 Hz, 2 H). MS ESI/APCI Dual posi: 172[M + H]⁺. Reference Example 5-3

¹H MR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.70 (m, 11 H) 1.99-2.13 (m, 2 H) 2.74 (s, 2 H) 4.18 (q, J = 7.1 Hz, 2 H). MS ESI/APCI Dual posi: 186[M + H]⁺. Reference Example 5-4

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.32 (t, J = 7.1 Hz, 3 H) 1.38-1.87 (m, 10 H) 1.99-2.15 (m, 2 H) 2.73 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H). MS ESI/APCI Dual posi: 200[M + H]⁺, 222[M + Na]⁺. Reference Example 5-5

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26-1.32 (m, 3 H) 1.42-1.54 (m, 2 H) 2.00-2.14 (m, 2 H) 2.79 (s, 2 H) 3.41-3.55 (m, 2 H) 3.80-3.90 (m, 2 H) 4.23 (q, J = 7.1 Hz, 2 H). MS ESI/APCI Dual posi: 188[M + H]⁺, 210[M + Na]⁺.

Reference Example 6-1 4-Cyclobutylbenzaldehyde

To a mixture of 4-iodobenzaldehyde (500 mg), bis(triphenylphosphine)palladium(II) dichloride (75.6 mg), copper(I) iodide (24.6 mg) and dehydrated tetrahydrofuran (10.0 mL), cyclobutylzinc bromide (0.5 mol/L, solution in tetrahydrofuran, 6.46 mL) was added and the mixture was stirred in a sealed tube at 60° C. for 14 hours. After cooling to room temperature, the precipitate was removed by filtration through Celite (registered trademark). The filtrate was concentrated under reduced pressure and thereafter purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-90:10) to give the titled compound as a colorless oil (225 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.79-2.28 (m, 4H) 2.29-2.48 (m, 2H) 3.54-3.73 (m, 1H) 7.32-7.39 (m, 2H) 7.74-7.87 (m, 2H) 9.97 (s, 1H).

MS ESI/APCI Dual posi: 161 [M+H]⁺.

Reference Example 6-2 4′-(Trifluoromethyl)biphenyl-4-carbaldehyde

A mixture of 4-bromobenzotrifluoride (10.0 g), 4-formylphenylboronic acid (7.33 g), tetrakis(triphenylphosphine)palladium(0) (308 mg), potassium carbonate (30.7 g), tetrahydrofuran (300 mL) and water (100 mL) was stirred at 85° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added to it, which was then extracted with ethyl acetate twice and the combined organic layers were washed with saturated brine. After adding anhydrous magnesium sulfate to the organic layers, the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in n-hexane (60 mL) with heating and thereafter cooled to 0° C. The resulting precipitate was recovered by filtration to give the titled compound as a gray solid (12.1 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.71-7.80 (m, 6H) 7.96-8.03 (m, 2H) 10.09 (s, 1H).

MS EI posi: 250 [M]

Reference Example 6-3 4′-Fluorobiphenyl-4-carbaldehyde

A mixture of 4-bromobenzaldehyde (10.0 g), 4-fluorophenylboronic acid (11.3 g), tetrakis(triphenylphosphine)palladium(0) (3.12 g), sodium carbonate (28.6 g), toluene (150 mL), ethanol (70.0 mL) and water (70.0 mL) was stirred at 100° C. for 12 hours. After cooling the reaction mixture to room temperature, water was added and extraction with toluene was conducted twice. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10) and after adding n-hexane to the residue, the mixture was stirred. The precipitate was recovered by filtration and dried under reduced pressure to give the titled compound as a colorless solid (10.4 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.12-7.22 (m, 2H) 7.56-7.66 (m, 2H) 7.68-7.75 (m, 2H) 7.93-7.98 (m, 2H) 10.06 (s, 1H).

MS ESI/APCI Dual posi: 201 [M+H]⁺.

Reference Example 6-4 4-Cyclopropyl-3-(trifluoromethyl)benzaldehyde

With 4-chloro-3-(trifluoromethyl)benzaldehyde (1.00 g) and cyclopropylboronic acid (1.24 g) being used as starting materials, the same technique as in Reference Example 6-3 was applied to give the titled compound as a pale yellow oil (900 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.85-0.95 (m, 2H) 1.13-1.25 (m, 2H) 2.23-2.37 (m, 1H) 7.13 (d, J=8.1 Hz, 1H) 7.94 (dd, J=8.1, 1.5 Hz, 1H) 8.12 (d, J=1.5 Hz, 1H) 10.00 (s, 1H).

MS ESI/APCI Dual posi: 215 [M+H]⁺.

MS ESI/APCI Dual nega: 213 [M−H]⁻.

Reference Example 6-5 3,3′-Bipyridine-6-carbaldehyde

A mixture of 5-bromo-3-pyridinecarboxyaldehyde (1.00 g), 3-pyridylboronic acid (991 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (220 mg), 2 mol/L sodium carbonate solution in water (5 mL), and N,N-dimethylformamide (20 mL) was stirred at 120° C. for 30 minutes under irradiation with microwaves.

After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine and thereafter passed through a phase separator for concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) to give the titled compound as a pale yellow solid (944 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.44-7.54 (m, 1H) 7.93-8.00 (m, 1H) 8.09 (d, J=1.6 Hz, 2H) 8.68-8.79 (m, 1H) 8.90-8.97 (m, 1H) 9.03 (t, J=1.6 Hz, 1H) 10.08-10.19 (m, 1H).

Reference Example 6-6 4-(6-Cyclopropyl-3-pyridinyl)benzaldehyde

A mixture of 3-bromo-6-(cyclopropyl)pyridine (2.00 g), 4-formylphenylboronic acid (1.82 g), palladium(II) acetate (113 mg), tripotassium phosphate (4.50 g) and ethylene glycol (16.8 mL) was stirred at 80° C. for 3 hours. After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine and thereafter the crude product was adsorbed on diatomaceous earth, with the solvent being distilled off under reduced pressure. The crude product adsorbed on the diatomaceous earth was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-50:50) to give the titled compound as a colorless solid (1.81 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.00-1.17 (m, 4H) 2.03-2.16 (m, 1H) 7.21-7.30 (m, 1H) 7.66-7.83 (m, 3H) 7.93-8.01 (m, 2H) 8.68-8.76 (m, 1H) 10.06 (s, 1H).

MS ESI/APCI Dual posi: 224 [M+H]⁺.

In the following Reference Examples 6-7 and 6-11, a commercial grade of the corresponding halogenated pyridines was used as the starting material and treated by the method described in Reference Example 6-6 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 3-1 below.

TABLE 3-1 Compound Salt No. Structure Analytical Data information Reference Example 6-7

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.06 (s, 3 H) 8.72-6.80 (m, 1 H) 7.38-7.47 (m, 1 H) 7.63-7.72 (m, 1 H) 7.92-8.00 (m, 2 H) 8.19-8.26 (m, 2 H) 10.03-10.12 (m, 1 H). MS ESl/APCI Dual posi: 214[M + H]⁺. Reference Example 6-8

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.74-7.82 (m, 1 H) 7.96-8.04 (m, 2 H) 8.10-8.20 (m, 2 H) 8.63-8.75 (m, 1 H) 10.09 (s, 1 H). MS ESI/APCI Dual posi: 218[M + H]⁺. Reference Example 6-9

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3 H) 7.27-7.35 (m, 1 H) 7.73-7.80 (m, 1 H) 7.91-8.01 (m, 2 H) 8.08-8.17 (m, 2 H) 8.41-8.48 (m, 1 H) 10.07 (s, 1 H). MS ESI/APCI Dual posi: 214[M + H]⁺. Reference Example 6-10

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3 H) 7.25-7.38 (m, 2 H) 7.92-7.99 (m, 2 H) 8.07-8.17 (m, 2 H) 8.31-8.39 (m, 1 H) 10.07 (s, 1 H). MS ESI/APCI Dual posi: 214[M + H]⁺. Reference Example 6-11

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3 H) 6.78-6.89 (m, 1 H) 7.28-7.33 (m, 1 H) 7.94-8.02 (m, 2 H) 8.10-8.18 (m, 2 H) 8.53-8.62 (m, 1H) 10.08 (s, 1 H). MS ESI/APCI Dual posi: 214[M + H]⁺.

Reference Example 7-1 4-Phenylcyclohexanecarbaldehyde

(1) Synthesis of [4-(methoxymethylidene)cyclohexyl]benzene

To a mixture of (methoxymethyl)triphenylphosphonium chloride (6.14 g) with tert-butyl methyl ether (30.0 mL), potassium tert-butoxide (2.32 g) was added, with the temperature in the system being held at −10° C. The mixture was stirred at −10° C. for 10 minutes and thereafter stirred at room temperature for an hour. A solution of 4-phenylcyclohexanone (2.4 0 g) in tetrahydrofuran (10.0 mL) was added, with the temperature in the system being held at −10° C. The mixture was stirred at −10° C. for 10 minutes and thereafter stirred at room temperature for two hours. After adding water, the mixture was extracted with ethyl acetate. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-60:40) to give [4-(methoxymethylidene)cyclohexyl]benzene as a colorless oil (3.59 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36-1.53 (m, 2H) 1.69-2.23 (m, 5H) 2.56-2.70 (m, 1H) 2.85-2.96 (m, 1H) 3.57 (s, 3H) 5.80-5.83 (m, 1H) 7.12-7.34 (m, 5H).

MS ESI/APCI Dual posi: 203 [M+H]⁺.

(2) Synthesis of the Titled Compound

To a solution in tetrahydrofuran (10.0 mL) of the compound (3.59 g) obtained in step (1) above, 3 mol/L hydrochloric acid was added and the mixture was refluxed for 4 hours. After cooling the reaction mixture to room temperature, water was added to it and three extractions were conducted with ethyl acetate. The combined organic layers were washed with water and then concentrated under reduced pressure to give the titled compound as a colorless oil (2.75 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13-1.62 (m, 4H) 1.63-2.19 (m, 4H) 2.23-2.40 (m, 1H) 2.42-2.60 (m, 1H) 7.10-7.39 (m, 5H) 9.65-9.82 (m, 1H).

MS EI posi: 188 [M]⁺.

Reference Example 8-1 4-(Cyclopropylmethoxy)benzaldehyde

To a mixture of 4-hydroxybenzaldehyde (2.00 g), potassium carbonate (4.53 g) and acetone (50.0 mL), (bromomethyl)cyclopropane (3.32 g) was added and the mixture was refluxed for 9 hours. After cooling the reaction mixture to room temperature, the resulting precipitate was removed by filtration through Celite (registered trademark). The filtrate was concentrated under reduced pressure and, thereafter, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-50:50) to give the titled compound as a colorless oil (2.63 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.34-0.42 (m, 2H) 0.62-0.73 (m, 2H) 1.21-1.37 (m, 1H) 3.89 (d, J=7.0 Hz, 2H) 6.96-7.04 (m, 2H) 7.80-7.86 (m, 2H) 9.88 (s, 1H).

MS ESI/APCI Dual posi: 177 [M+H]⁺, 199 [M+Na]⁺.

In the following Reference Examples 8-2 to 8-5, a commercial grade each of the corresponding phenols and halogenated alkanes was used and treated by the method described in Reference Example 8-1 or modifications thereof to give the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 4-1.

TABLE 4-1 Compound Salt No. Structure Analytical Data information Reference Example 8-2

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.36-0.45 (m, 2 H) 0.65-0.78 (m, 2 H) 1.27-1.42 (m, 1 H) 3.97 (d, J = 7.0 Hz, 2 H) 7.00-7.10 (m, 1 H) 7.56-7.68 (m, 2 H) 9.33-9.88 (m, 1 H). MS ESI/APCI Dual posi: 195[M + H]⁺. Reference Example 8-3

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.35-0.43 (m, 2 H) 0.60-0.71 (m, 2 H) 1.20-1.39 (m, 1 H) 2.29 (s, 3 H) 3.92 (d, J = 6.7 Hz, 2 H) 6.83-6.91 (m, 1 H) 7.61-7.73 (m, 2 H) 9.84 (s, 1 H). MS ESI/APCI Dual posi: 191[M + H]⁺, 213[M + Na]⁺. Reference Example 8-4

¹H HMR (300 MHz, CHLOROFORM-d) δ ppm 5.11 (s, 2 H) 7.02-7.15 (m, 4 H) 7.37-7.46 (m, 2 H) 7.79-7.90 (m, 2 H) 9.90 (s, 1 H). MS ESI/APCI Dual posi: 231[M + H]⁺. MS ESI/APCI Dual nega: 229[M − H]⁻. Reference Example 8-5

¹H NMR: (300 MHz, CHLOROFORM-d) δ ppm 5.12 (s, 2 H) 7.02-7.10 (m, 2 H) 7.38 (s, 4 H) 7.81-7.89 (m, 2 H) 9.90 (s, 1 H). MS ESI/APCI Dual posi: 247[M + H]⁺. MS ESI/APCI Dual nega: 245[M − H]⁻.

Reference 9-1 4-(Cyclobutylmethoxy)benzaldehyde

To a suspension of sodium hydride (60% dispersion in mineral oil, 0.328 g) in N,N-dimethylformamide (15.0 mL), a solution of 4-hydroxybenzaldehyde (1.00 g) in N,N-dimethylformamide (5.00 mL) was added at 0° C. and thereafter the mixture was stirred at room temperature for 30 minutes. After adding (bromomethyl)cyclobutane (1.22 g), the mixture was stirred at 70° C. for 24 hours. After cooling the reaction mixture to room temperature, 0.5 mol/L hydrochloric acid was added under cooling with ice and three extractions were conducted with ethyl acetate. The combined organic layers were passed through a phase separator and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-40:60) to give the titled compound as a colorless oil (1.19 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.79-2.04 (m, 4H) 2.08-2.26 (m, 2H) 2.72-2.91 (m, 1H) 4.01 (d, J=6.7 Hz, 2H) 6.88-7.07 (m, 2H) 7.77-7.87 (m, 2H) 9.88 (s, 1H).

In the following Reference Examples 9-2 and 9-3, (bromomethyl)cyclobutane was replaced by a commercial grade of the corresponding halogenated alkane or halogenated cycloalkane and the method described in Reference Example 9-1 or a modification thereof was applied to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 5-1 below.

TABLE 5-1 Compound No. Structure Analytical Data Salt information Reference Example 9-2

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29-1.44 (m, 2 H) 1.50-1.74 (m, 4 H) 1.78-1.96 (m, 2 H) 2.30-2.48 (m, 1 H) 3.92 (d, J = 7.0 Hz, 2 H) 6.95-7.03 (m, 2 H) 7.79-7.86 (m, 2 H) 9.88 (s, 1 H). MS ESI/APCI Dual posi: 205[M + H]⁺. Reference Example 9-3

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.54-2.06 (m, 8 H) 4.80-5.11 (m, 1 H) 6.93-7.00 (m, 2 H) 7.77-7.85 (m, 2 H) 9.87 (s, 1 H). MS ESI/APCI Dual posi: 191[M + H]⁺.

Reference Example 10-1 4-(Cyclopropoxy)benzaldehyde

To a mixture of 4-hydroxybenzaldehyde (1.20 g), potassium carbonate (2.04 g), potassium iodide (49.0 mg) and N,N-dimethylformamide (9.80 mL), bromocyclopropane (1.02 mL) was added and the mixture was stirred at 200° C. for 3 hours under irradiation with microwaves. After being cooled to room temperature, the reaction mixture was poured into water and extracted with diethyl ether three times. The combined organic layers were washed with saturated brine and thereafter passed through a phase separator to be concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) to give the titled compound as a colorless oil (510 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.76-0.91 (m, 4H) 3.77-3.88 (m, 1H) 7.12-7.19 (m, 2H) 7.80-7.87 (m, 2H) 9.90 (s, 1H).

MS ESI/APCI Dual posi: 163 [M+H]⁺, 185 [M+Na]⁺.

In the following Reference Examples 10-2 to 10-5, bromo cyclopropane was replaced by a commercial grade of the corresponding halogenated alkanes and the method described in Reference Example 10-1 or a modification thereof was applied to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 6-1 below.

TABLE 6-1 Compound Salt No. Structure Analytical Data information Reference Example 10-2

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.63-1.82 (m, 1 H) 1.83-1.98 (m, 1 H) 2.11-2.30 (m, 2 H) 2.42-2.56 (m, 2 H) 4.73 (quin, J = 7.3 Hz, 1 H) 6.87-6.94 (m, 2 H) 7.77-7.85 (m, 2 H) 9.87 (s, 1 H). MS ESI/APCI Dual posi: 177[M + H]⁺, 199[M + Na]⁺. Reference Example 10-3

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.37 (s, 3 H) 5.20 (s, 2 H) 7.08-7.15 (m, 1 H) 7.18-7.24 (m, 2 H) 7.30-7.36 (m, 2 H) 7.57-7.66 (m, 2 H) 9.85 (d, J = 2.2 Hz, 1 H). MS ESI/APCI Dual posi: 267[M + Na]⁺. MS ESI/APCI Dual nega: 243[M − H]⁻. Reference Example 10-4

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.32 (s, 3 H) 5.14 (s, 2 H) 6.95-7.01 (m, 1 H) 7.05-7.15 (m, 2 H) 7.38-7.45 (m, 2 H) 7.67-7.73 (m, 2 H) 9.87 (s, 1 H). MS ESI/APCI Dual posi: 245[M + H]⁺, 267[M + Na]⁺. MS ESI/APCI Dual nega: 243[M − H]⁻. Reference Example 10-5

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.33 (s, 3 H) 5.17 (s, 2 H) 6.94-7.01 (m, 1 H) 7.22-7.31 (m, 2 H) 7.44-7.52 (m, 2 H) 7.68-7.76 (m, 2 H) 9.87 (s, 1 H). MS ESI/APCI Dual posi: 311[M + H]⁺, 333[M + Na]⁺. MS ESI/APCI Dual nega: 309[M − H]⁻.

Reference Example 11-1 4-(2-Cyclopropylethoxyl)benzaldehyde

To a mixture of 4-hydroxybenzaldehyde (2.84 g), 2-cyclopropylethanol (2.00 g), triphenylphosphine (6.09 g) and tetrahydrofuran (100 mL), diethyl azodicarboxylate (2.2 mol/L, solution in toluene, 10.5 mL) was added and the mixture was stirred at room temperature for 4 days. After concentrating the reaction mixture under reduced pressure, ethyl acetate (7.50 mL) and n-hexane (143 mL) were added and the mixture was stirred at room temperature for 15 minutes. The precipitate was removed by filtration through Celite (registered trademark). The filtrate was concentrated under reduced pressure and, thereafter, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-50:50) to give the titled compound as a yellow oil (3.34 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.10-0.18 (m, 2H) 0.46-0.55 (m, 2H) 0.78-0.95 (m, 1H) 1.67-1.76 (m, 2H) 4.12 (t, J=6.6 Hz, 2H) 6.97-7.05 (m, 2H) 7.80-7.87 (m, 2H) 9.88 (s, 1H).

MS ESI posi: 191 [M+H]⁺.

In the following Reference Examples 11-2 to 11-11, a commercial grade of the corresponding hydroxybenzaldehydes and a commercial grade of the corresponding alcohols were used and treated by the method described in Reference Example 11-1 or modifications thereof to give the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Tables 7-1 and 7-2.

TABLE 7-1 Compound Salt No. Structure Analytical Data information Reference Example 11-2

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.59 (s, 3 H) 5.25 (s, 2 H) 7.06-7.14 (m, 3 H) 7.29 (d, J = 7.8 Hz, 1 H) 7.62 (t, J = 7.8 Hz, 1 H) 7.81-7.88 (m, 2 H) 9.89 (s, 1 H). MS ESI/APCI Dual posi: 228[M + H]⁺, 250[M + Na]⁺, MS ESI/APCI Dual nega: 226[M − H]⁻. Reference Example 11-3

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.27 (s, 3 H) 2.59- 2.78 (m, 2 H) 4.30 (t, J = 6.3 Hz, 2 H) 6.91 (d, J = 8.9 Hz, 1 H) 7.66-7.77 (m, 2 H) 9.87 (s, 1 H). MS ESI/APCI Dual posi: 233[M + H]⁺. Reference Example 11-4

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.59-2.85 (m, 2 H) 4.25-4.43 (m, 2 H) 7.00-7.15 (m, 1 H) 7.56-7.70 (m, 2 H) 9.82-9.96 (m, 1 H). Reference Example 11-5

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.34 (s, 3 H) 2.46 (s, 3 H) 4.96 (s, 2 H) 7.11 (d, J = 8.4 Hz, 1 H) 7.80 (dd, J = 8.4, 2.0 Hz, 1 H) 7.94 (d, J = 2.0 Hz, 1 H) 9.88 (s, 1 H). MS ESI/APCI Dual posi: 266[M + H]⁺, 288[M + Na]⁺. MS ESI/APCI Dual nega: 264[M − H]⁻, 300[M + Cl]⁻. Reference Example 11-6

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.36 (s, 3 H) 2.42 (s, 3 H) 5.08 (s, 2 H) 7.23 (d, J = 8.5 Hz, 1 H) 7.76 (dd, J = 8.5, 2.0 Hz, 1 H) 7.91 (d, J = 2.0 Hz, 1 H) 9.86 (s, 1 H). MS ESI/APCI Dual posi: 266[M + H]⁺, 288[M + Na]⁺. MS ESI/APCI Dual nega: 264[M − H]⁻. Reference Example 11-7

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.59 (s, 3 H) 5.13 (s, 2 H) 7.05-7.11 (m, 2 H) 7.18-7.24 (m, 1 H) 7.69-7.72 (m, 1 H) 7.83-7.89 (m, 2 H) 8.55-8.59 (m, 1 H) 9.90 (s, 1 H). MS ESI/APCI Dual posi: 228[M + H]⁺. MS ESI/APCI Dual nega: 226[M − H]⁻.

TABLE 7-2 Compound Salt No. Structure Analytical Data information Reference Example 11-8 

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.61 (s, 3 H) 5.14 (s, 2 H) 7.06-7.13 (m, 2 H) 7.19 (dd, J = 7.7, 4.8 Hz, 1 H) 7.71- 7.75 (m, 1 H) 7.85-7.91 (m, 2 H) 8.51 (dd, J = 4.8, 1.7 Hz, 1 H) 9.92 (s, 1 H). MS ESI/APCI Dual posi: 228[M + H]⁺. MS ESI/APCI Dual nega: 226[M − H]⁻. Reference Example 11-9 

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 5.26 (s, 2 H) 7.06- 7.12 (m, 2 H) 7.45-7.50 (m, 1 H) 7.72 (dd, J = 8.5, 2.3 Hz, 1 H) 7.82-7.88 (m, 2 H) 8.58 (d, J = 2.3 Hz, 1 H) 9.90 (s, 1 H). MS ESI/APCI Dual posi: 248[M + H]⁺. Reference Example 11-10

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.46-2.50 (m, 3 H) 5.38 (s, 2 H) 7.09-7.15 (m, 2 H) 7.43-7.46 (m, 1 H) 7.82- 7.88 (m, 2 H) 9.90 (s, 1 H). MS ESI/APCI Dual posi: 234[M + H]⁺. Reference Example 11-11

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 5.22 (s, 2 H) 6.86 (d, J = 4.5 Hz, 1 H) 7.11-7.17 (m, 2 H) 7.41 (d, J = 4.5 Hz, 1 H) 7.55 (s, 1 H) 7.81-7.88 (m, 2 H) 9.89 (s, 1 H). MS ESI/APCI Dual posi: 259[M + H]⁺.

Reference Example 12-1

3-Fluoro-4-(2,2,2-trifluoroethoxyl)benzaldehyde

To a suspension of sodium hydride (60% dispersion in mineral oil, 0.844 g) in N,N-dimethylfounamide (30.0 mL), 2,2,2-trifluoroethanol (2.11 g) was added at 0° C. and thereafter the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, a solution of 3,4-difluorobenzaldehyde (2.00 g) in N,N-dimethylformamide (10.0 mL) was added and thereafter the mixture was stirred at room temperature for 30 minutes. After adding 1 mol/L hydrochloric acid at 0° C., three extractions were conducted with ethyl acetate. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=80:20-30:70) to give the titled compound as a colorless oil (2.50 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.52 (q, J=7.9 Hz, 2H) 7.11-7.19 (m, 1H) 7.63-7.71 (m, 2H) 9.89-9.91 (m, 1H).

MS EI posi: 222 [M]⁺.

In the following Reference Examples 12-2 to 12-9, a commercial grade of the corresponding fluorobenzaldehydes and a commercial grade of the corresponding alcohols were used and treated by the method described in Reference Example 12-1 or modifications thereof to give the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Tables 8-1 and 8-2.

TABLE 8-1 Compound Salt No. Structure Analytical Data information Reference Example 12-2

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 4.44 (q, J = 7.9 Hz, 2 H) 7.04-7.11 (m, 2 H) 7.86-7.92 (m, 2 H) 9.93 (s, 1 H). MS ESI/APCI Dual posi: 205[M + H]⁺. Reference Example 12-3

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 4.51 (q, J = 7.8 Hz, 2 H) 7.03-7.09 (m, 1 H) 7.78-7.82 (m, 1 H) 7.94-7.98 (m, 1 H) 9.90 (s, 1 H). MS ESI/APCI Dual posi: 239[M + H]⁺. Reference Example 12-4

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.01-2.20 (m, 2 H), 2.23-2.46 (m, 2 H) 4.11 (t, J = 6.0 Hz, 2 H) 6.93-7.06 (m, 2 H) 7.79-7.91 (m, 2 H) 9.90 (s, 1 H). MS ESI/APCI Dual posi: 233[M + H]⁺. Reference Example 12-5

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.06-2.20 (m, 2 H) 2.22-2.45 (m, 5 H) 4.13 (t, J = 6.0 Hz, 2 H) 6.87-6.93 (m, 1 H) 7.65-7.75 (m, 2 H) 9.86 (s, 1 H). MS ESI/APCI Dual posi: 247[M + H]⁺. Reference Example 12-6

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.09-2.21 (m, 2 H) 2.27-2.46 (m, 2 H) 4.19 (t, J = 6.0 Hz, 2 H) 7.02-7.10 (m, 1 H) 7.59-7.67 (m, 2 H) 9.85-9.88 (m, 1 H). MS ESI/APCI Dual posi: 251[M + H]⁺. Reference Example 12-7

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 4.62-4.72 (m, 2 H) 4.75-4.98 (m, 3 H) 7.18 (d, J = 8.5 Hz, 1 H) 7.77 (d, J = 8.5, 2.1 Hz, 1 H) 7.94 (d, J = 2.1 Hz, 1 H) 9.88 (s, 1 H). MS ESI/APCI Dual posi: 235[M + H]⁺. Reference Example 12-8

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.30 (s, 3 H) 4.59- 4.67 (m, 2 H) 4.74-4.94 (m, 3 H) 6.98-7.04 (m, 1 H) 7.68- 7.74 (m, 2 H) 9.88 (s, 1 H). MS ESI/APCI Dual posi: 215[M + H]⁺.

TABLE 8-2 Compound Salt No. Structure Analytical Data information Reference Example 12-9

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.32 (s, 3 H) 4.45 (q, J = 7.9 Hz, 2 H) 6.83-6.97 (m, 1 H) 7.66-7.80 (m, 2 H) 9.90 (s, 1 H). MS ESI/APCI Dual posi: 219[M + H]⁺.

Reference Example 13-1 6-[4-(Trifluoromethyl)phenoxy]pyridin-3-carbaldehyde

To a solution of 4-hydroxybenzotrifluoride (505 mg) in N,N-dimethylforamide (5.00 L), potassium carbonate (474 mg) was added and the mixture was stirred at room temperature for 10 minutes.

Subsequently, 6-bromo-3-pyridinecarboxyaldehyde (580 mg) was added and the mixture was stirred at 130° C. for 2 hours. After cooling the mixture to room temperature, water was added to the mixture, which was then extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine successively and after passage through a phase separator, they were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-70:30) to give the titled compound as a colorless solid (605 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.09-7.15 (m, 1H) 7.27-7.33 (m, 2H) 7.66-7.75 (m, 2H) 8.24 (dd, J=8.5, 2.3 Hz, 1H) 8.62 (dd, J=2.3, 0.6 Hz, 1H) 9.99-10.02 (m, 1H).

MS ESI/APCI Dual posi: 268 [M+H]⁺.

In the following Reference Examples 13-2 to 13-36, a commercial grade of the corresponding phenols or hydroxypyridines and a commercial grade of the corresponding halogenated benzaldehydes or halogenated pyridinecarboxyaldehydes were used and treated by the method described in Reference Example 13-1 or modifications thereof to give the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Tables 9-1 and 9-5.

TABLE 9-1 Compound Salt No. Structure Analytical Data information Reference Example 13-2

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.05 (dd, J = 8.5, 1.1 Hz, 1 H) 7.09-7.18 (m, 4 H) 8.20 (dd, J = 8.5, 2.3 Hz, 1 H) 8.61 (dd, J = 2.3, 0.6 Hz, 1 H) 9.99 (s, 1 H). MS ESI/APCI Dual posi: 218[M + H]⁺. MS ESI/APCI Dual nega: 216[M − H]⁻. Reference Example 13-3

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 6.97-7.24 (m, 3 H) 7.33-7.45 (m, 2 H) 8.21 (dd, J = 8.6, 2.4 Hz, 1 H) 8.61 (d, J = 2.4 Hz, 1 H) 9.99 (d, J = 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 234[M + H]⁺. MS ESI/APCI Dual nega: 232[M − H]⁻. Reference Example 13-4

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.39 (s, 3 H) 6.90- 7.04 (m, 3 H) 7.09 (dd, J = 7.4, 0.9 Hz, 1 H) 7.27-7.39 (m, 1 H) 8.18 (dd, J = 8.6, 2.4 Hz, 1 H) 8.64 (d, J = 2.4 Hz, 1 H) 9.98 (s, 1 H). MS ESI/APCI Dual posi: 214[M + H]⁺. MS ESI/APCI Dual nega: 212[M − H]⁻. Reference Example 13-5

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 6.85-7.13 (m, 4 H) 7.33-7.51 (m, 1 H) 8.22 (dd, J = 8.5, 2.3 Hz, 1 H) 8.58- 8.70 (m, 1 H) 10.00 (d, J = 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 218[M + H]⁺. MS ESI/APCI Dual nega: 216[M − H]⁻. Reference Example 13-6

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.13 (dt, J = 8.6, 0.7 Hz, 1 H) 7.17-7.32 (m, 4 H) 8.22 (dd, J = 8.6, 2.3 Hz, 1 H) 8.59 (dd, J = 2.3, 0.7 Hz, 1 H) 9.99 (d, J = 0.7 Hz, 1 H). MS ESI/APCI Dual posi: 218[M + H]⁺. Reference Example 13-7

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.16 (s, 3 H) 6.97- 7.04 (m, 1 H) 7.05-7.11 (m, 1 H) 7.14-7.38 (m, 3 H) 8.18 (dd, J = 8.5, 2.3 Hz, 1 H) 8.61 (dd, J = 2.3, 0.6 Hz, 1 H) 9.97 (s, 1 H). MS ESI/APCI Dual posi: 214[M + H]⁺. Reference Example 13-8

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.03-7.11 (m, 2 H) 7.21 (t, J = 2.3 Hz, 1 H) 7.23-7.29 (m, 1 H) 7.34-7.41 (m, 1 H) 8.21 (dd, J = 8.5, 2.3 Hz, 1 H) 8.63 (dd, J = 2.3, 0.6 Hz, 1 H) 10.00 (d, J = 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 234[M + H]⁺. MS ESI/APCI Dual nega: 232[M − H]⁻.

TABLE 9-2 Compound Salt No. Structure Analytical Data information Reference Example 13-9 

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.07-7.14 (m, 1 H) 7.30-7.42 (m, 1 H) 7.43-7.48 (m, 1 H) 7.50-7.63 (m, 2 H) 8.24 (dd, J = 8.5, 2.4 Hz, 1 H) 8.62 (dd, J = 2.4, 0.6 Hz, 1 H) 10.01 (d, J = 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 268[M + H]⁺. Reference Example 13-10

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.04-7.18 (m, 4 H) 7.40-7.51 (m, 1 H) 8.23 (dd, J = 8.7, 2.3 Hz, 1 H) 8.63 (dd, J = 2.3, 0.6 Hz, 1 H) 10.00 (d, J = 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 284[M + H]⁺. Reference Example 13-11

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.39 (s, 3 H) 6.94- 7.10 (m, 3 H) 7.19-7.31 (m, 2 H) 8.17 (dd, J = 8.6, 2.4 Hz, 1 H) 8.62 (dd, J = 2.4, 0.6 Hz, 1 H) 9.97 (d, J = 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 214[M + H]⁺. MS ESI/APCI Dual nega: 212[M − H]⁻. Reference Example 13-12

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.37 (s, 3 H) 6.82- 6.94 (m, 2 H) 6.99-7.06 (m, 3 H) 7.24-7.33 (m, 1 H) 7.79- 7.88 (m, 2 H) 9.92 (s, 1 H). MS ESI/APCI Dual posi: 213[M + H]⁺. MS ESI/APCI Dual nega: 211[M − H]⁻. Reference Example 13-13

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 6.75-6.99 (m, 3 H) 7.05-7.15 (m, 2 H) 7.29-7.42 (m, 1 H) 7.83-7.91 (m, 2 H) 9.95 (s, 1 H). MS ESI/APCI Dual posi: 217[M + H]⁺. MS ESI/APCI Dual nega: 215[M − H]⁻. Reference Example 13-14

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 6.96-7.12 (m, 4 H) 7.30-7.42 (m, 2 H) 7.80-7.90 (m, 2 H) 9.93 (s, 1 H). MS ESI/APCI Dual posi: 233[M + H]⁺. Reference Example 13-15

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.04-7.19 (m, 4 H) 7.29 (ddd, J = 8.7, 2.8, 0.9 Hz, 1 H) 7.88-7.98 (m, 1 H) 8.49 (d, J = 2.8 Hz, 1 H) 10.02 (d, J = 0.9 Hz, 1 H). MS ESI/APCI Dual posi: 218[M + H]⁺, 240[M + Na]⁺. MS ESI/APCI Dual nega: 216[M − H]⁻.

TABLE 9-3 Compound Salt No. Structure Analytical Data information Reference Example 13-16

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.38 (s, 3 H) 6.93- 7.06 (m, 2 H) 7.17-7.23 (m, 3 H) 7.92 (dd, J = 8.7, 0.9 Hz, 1 H) 8.49 (d, J = 2.6 Hz, 1 H) 10.01 (d, J = 0.9 Hz, 1 H). MS ESI/APCI Dual posi: 214[M + H]⁺, 236[M + Na]⁺. Reference Example 13-17

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.59 (s, 3 H) 7.00- 7.10 (m, 2 H) 7.17-7.24 (m, 1 H) 7.29-7.36 (m, 1 H) 7.81- 7.92 (m, 2 H) 8.35 (d, J = 2.8 Hz, 1 H) 9.94 (s, 1 H). MS ESI/APCI Dual posi: 214[M + H]⁺. Reference Example 13-18

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 6.99-7.09 (m, 2 H) 7.13-7.20 (m, 4 H) 7.77-7.92 (m, 2 H) 9.93 (s, 1 H). MS ESI/APCI Dual posi: 217[M + H]⁺. MS ESI/APCI Dual nega: 215[M − H]⁻. Reference Example 13-19

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.18 (s, 3 H) 6.99- 7.04 (m, 3 H) 7.11-7.35 (m, 3 H) 7.77-7.88 (m, 2 H) 9.91 (s, 1 H). MS ESI/APCI Dual posi: 213[M + H]⁺. MS ESI/APCI Dual nega: 211[M − H]⁻. Reference Example 13-20

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 3.80 (s, 3 H) 6.62- 6.71 (m, 2 H) 6.77 (ddd, J = 8.3, 2.4, 0.9 Hz, 1 H) 7.04- 7.11 (m, 2 H) 7.27-7.34 (m, 1 H) 7.80-7.92 (m, 2 H) 9.93 (s, 1 H). MS ESI/APCI Dual posi: 229[M + H]⁺. MS ESI/APCI Dual nega: 227[M − H]⁻. Reference Example 13-21

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 6.84 (dd, J = 8.4, 0.8 Hz, 1 H) 7.00-7.23 (m, 5 H) 7.42-7.58 (m, 1 H) 7.93 (dd, J = 7.5, 1.6 Hz, 1 H) 10.53 (d, J = 0.8 Hz, 1 H). MS ESI/APCI Dual posi: 217[M + H]⁺, 239[M + Na]⁺. MS ESI/APCI Dual nega: 215[M − H]⁻.

TABLE 9-4 Compound Salt No. Structure Analytical Data information Reference Example 13-22

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.04 (d, J = 9.0 Hz, 2 H) 7.29-7.36 (m, 1 H) 7.37-7.45 (m, 2 H) 7.96 (dd, J = 9.0, 0.6 Hz, 1 H) 8.51 (dd, J = 2.6, 0.6 Hz, 1 H) 10.02 (d, J = 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 234[M + H]⁺, 256[M + Na]⁺. MS ESI/APCI Dual nega: 232[M − H]⁻. Reference Example 13-23

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 3.82 (s, 3 H) 6.70- 6.79 (m, 2 H) 6.80-6.87 (m, 1 H) 7.03 (d, J = 8.5 Hz, 1 H) 7.34 (t, J = 8.5 Hz, 1 H) 8.18 (dd, J = 8.5, 2.4 Hz, 1 H) 8.65 (dd, J = 2.4, 0.7 Hz, 1 H) 9.98 (d, J = 0.7 Hz, 1 H). MS ESI/APCI Dual posi: 230[M + H]⁺. MS ESI/APCI Dual nega: 228[M − H]⁻. Reference Example 13-24

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.10 (d, J = 8.5 Hz, 2 H) 7.36-7.42 (m, 2 H) 7.86-7.96 (m, 2 H) 8.24 (dd, J = 2.4, 1.2 Hz, 1 H) 9.96 (s, 1 H). MS ESI/APCI Dual posi: 234[M + H]⁺. Reference Example 13-25

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.19 (d, J = 8.5 Hz, 2 H) 7.36-7.48 (m, 1 H) 7.70 (d, J = 8.5 Hz, 2 H) 8.00 (d, J = 8.5 Hz, 1 H) 8.56 (d, J = 2.6 Hz, 1 H) 10.05 (d, J = 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 268[M + H]⁺, 290[M + Na]⁺. Reference Example 13-26

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.11-7.23 (m, 2 H) 7.43-7.56 (m, 1 H) 7.67-7.80 (m, 1 H) 7.95 (d, J = 8.9 Hz, 2 H) 8.49-8.57 (m, 1 H) 9.99 (s, 1 H). MS ESI/APCI Dual posi: 268[M + H]⁺. Reference Example 13-27

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.39 (s, 3 H) 6.95- 7.09 (m, 2 H) 7.18-7.21 (m, 1 H) 7.25-7.31 (m, 1 H) 8.20 (dd, J = 8.6, 2.4 Hz, 1 H) 8.62 (dd, J = 2.4, 0.6 Hz, 1 H) 9.98 (s, 1 H). MS ESI/APCI Dual nega: 246[M − H]⁻. Reference Example 13-28

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.29 (d, J = 2.0 Hz, 3 H) 6.80-6.92 (m, 2 H) 7.00-7.09 (m, 1 H) 7.17-7.30 (m, 1 H) 8.13-8.27 (m, 1 H) 8.56-8.68 (m, 1 H) 9.98 (s, 1 H). MS EI posi: 231[M].

TABLE 9-5 Com- pound Salt No. Structure Analytical Data information Refer- ence Exam- ple 13-29

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.30 (d, J = 2.4 Hz, 3 H) 6.89-7.14 (m, 4 H) 8.19 (dd, J = 8.6, 2.4 Hz, 1 H) 8.62 (dd, J = 2.4, 0.6 Hz, 1 H) 9.98 (d, J = 0.6 Hz, 1 H). MS ESI/APCI Dual nega: 230[M − H]⁻. Refer- ence Exam- ple 13-30

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.24-1.31 (m, 3 H) 2.63-2.75 (m, 2 H) 6.98-7.13 (m, 3 H) 7.23-7.32 (m, 2 H) 8.13-8.22 (m, 1 H) 8.60-8.86 (m, 1 H) 9.95-9.99 (m, 1 H). MS ESI/APCI Dual posi: 228[M + H]⁺. Refer- ence Exam- ple 13-31

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.98 (t, J = 7.4 Hz, 3 H) 1.58-1.76 (m, 2 H) 2.56-2.68 (m, 2 H) 6.95-7.14 (m, 3 H) 7.17-7.35 (m, 2 H) 8.17 (dd, J = 8.6, 2.3 Hz, 1 H) 8.63 (dd, J = 2.3, 0.6 Hz, 1 H) 9.98 (s, 1 H). MS ESI/APCI Dual posi: 242[M + H]⁺. Refer- ence Exam- ple 13-32

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.28 (d, J = 6.8 Hz, 6 H) 2.88-3.03 (m, 1 H) 6.99-7.04 (m, 1 H) 7.05-7.12 (m, 2 H) 7.21-7.37 (m, 2 H) 8.17 (dd, J = 8.6, 2.4 Hz, 1 H) 8.64 (dd, J = 2.4, 0.6 Hz, 1 H) 9.98 (s, 1 H). MS ESI/APCI Dual posi: 242[M + H]⁺. Refer- ence Exam- ple 13-33

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.39 (s, 3 H) 7.01- 7.09 (m, 2 H) 7.22-7.29 (m, 2 H) 8.20-8.27 (m, 1 H) 8.42- 8.48 (m, 1 H) 9.94 (s, 1 H). MS ESI/APCI Dual posi: 248[M + H]⁺. Refer- ence Exam- ple 13-34

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.39 (s, 3 H) 7.00- 7.07 (m, 2 H) 7.21-7.30 (m, 2 H) 7.91 (dd, J = 5.3, 1.9 Hz, 1 H) 8.36 (d, J = 1.9 Hz, 1 H) 9.97 (d, J = 2.6 Hz, 1 H). MS ESI/APCI Dual posi: 232[M + H]⁺. Refer- ence Exam- ple 13-35

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.43 (s, 3 H) 7.07- 7.14 (m, 2 H) 7.34-7.46 (m, 2 H) 8.03 (dd, J = 2.3, 0.9 Hz, 1 H) 8.40 (d, J = 2.3 Hz, 1 H) 9.94 (s, 1 H). MS ESI/APCI Dual posi: 248[M + H]⁺. Refer- ence Exam- ple 13-36

¹H NMR (200 MHz, CHLOROFORM-d ) δ ppm 2.45 (s, 3 H) 2.60 (s, 3 H) 7.21-7.26 (m, 1 H) 7.39-7.48 (m, 1 H) 8.01-8.06 (m, 1 H) 8.36-8.41 (m, 2 H) 9.95 (s, 1 H). MS ESI/APCI Dual posi: 229[M + H]⁺.

Reference Example 13-37 6-(4-Cyclopropylphenoxyl)pyridine-3-carbaldehyde

(1) Synthesis of 6-(4-bromophenoxy)pyridine-3-carbaldehyde

To a solution of 4-bromophenol (2.79 g) in N,N-dimethylfomamide (25.0 mL), potassium carbonate (2.45 g) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, 6-bromo-3-pyridinecarboxyaldehyde (3.00 g) was added and the mixture was stirred at 130° C. for 2.5 hours. After cooling the reaction mixture to room temperature, water was added to it and extraction was conducted with ethyl acetate. The combined organic layers were washed with water and saturated brine successively and after passage through a phase separator, they were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) to give 6-(4-bromophenoxy)pyridine-3-carbaldehyde as a pale yellow solid (3.23 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.01-7.13 (m, 3H) 7.51-7.61 (m, 2H) 8.21 (dd, J=8.6, 2.4 Hz, 1H) 8.61 (dd, J=2.4, 0.7 Hz, 1H) 9.99 (d, J=0.7 Hz, 1H).

MS ESI/APCI Dual posi: 278 [M+H]⁺.

(2) Synthesis of the Titled Compound

A mixture of the compound (3.22 g) obtained in step (1) above, 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.89 g), tetrakis(triphenylphosphine)palladium(0) (669 mg), cesium carbonate (11.3 g), toluene (20.0 mL) and water (10.0 mL) was stirred at 100° C. for 6 hours. After cooling the reaction mixture to room temperature, the precipitate was removed by filtration through Celite (registered trademark). To the filtrate, water and ethyl acetate were added and extraction was conducted with ethyl acetate. The combined organic layers were washed with water and saturated brine successively and after passage through a phase separator, they were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) and further purified by preparative HPLC. A saturated aqueous solution of sodium hydrogencarbonate was then added and extraction was conducted with ethyl acetate. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure to give the titled compound as a colorless oil (614 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.65-0.76 (m, 2H) 0.92-1.04 (m, 2H) 1.84-1.98 (m, 1H) 6.94-7.10 (m, 3H) 7.11-7.20 (m, 2H) 8.17 (dd, J=8.6, 2.4 Hz, 1H) 8.60-8.67 (m, 1H) 9.97 (d, J=0.6 Hz, 1H).

MS ESI/APCI Dual posi: 240 [M+H]⁺.

MS ESI/APCI Dual nega: 238 [M−H]⁻.

Reference Example 14-1 4-[(5-Fuoropyridin-2-yl)oxy]benzaldehyde

To a solution of 4-hydroxybenzaldehyde (5.00 g) in N,N-dimethylacetamide (60.0 L), potassium carbonate (6.23 g) was added and the mixture was stirred at room temperature for 10 minutes. Subsequently, 2,5-difluoropyridine (4.71 g) was added and the mixture was stirred at 150° C. for 64 hours. After cooling the reaction mixture to room temperature, water was added to it and extraction was conducted with ethyl acetate. The combined organic layers were washed with water and saturated brine successively and after passage through a phase separator, they were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-70:30) to give the titled compound as a colorless solid (3.24 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.98-7.05 (m, 1H) 7.21-7.29 (m, 2H) 7.46-7.57 (m, 1H) 7.89-7.96 (m, 2H) 8.05-8.09 (m, 1H) 9.98 (s, 1H).

MS ESI/APCI Dual posi: 218 [M+H]⁺.

In the following Reference Examples 14-2 to 14-4, a commercial grade of the corresponding halogenated pyridines was used and treated by the method described in Reference Example 14-1 or modifications thereof to give the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 10-1.

TABLE 10-1 Compound Salt No. Structure Analytical Data information Reference Example 14-2

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 6.93-7.03 (m, 1 H) 7.20-7.32 (m, 2 H) 7.66-7.78 (m, 1 H) 7.88-7.98 (m, 2 H) 8.14-8.19 (m, 1 H) 9.99 (s, 1 H). MS ESI/APCI Dual posi: 234[M + H]⁺. Reference Example 14-3

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.32 (s, 3 H) 6.92 (d, J = 7.9 Hz, 1 H) 7.18-7.30 (m, 2 H) 7.54-7.62 (m, 1 H) 7.85-7.95 (m, 2 H) 8.06 (dt, J = 2.5, 0.7 Hz, 1 H) 9.96 (s, 1 H). MS ESI/APCI Dual posi: 214[M + H]⁺, 236[M + Na]⁺. Reference Example 14-4

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 7.12 (dt, J = 8.6, 0.7 Hz, 1 H) 7.29-7.35 (m, 2 H) 7.94-8.01 (m, 3 H) 8.41- 8.49 (m, 1 H) 10.02 (s, 1 H), MS ESI/APCI Dual posi: 268[M + H]⁺.

Reference 14-5 4-[(5-cyclopropylpyridin-2-yl)oxy]benzaldehyde

(1) Synthesis of 4-[(5-bromopyridin-2-yl)oxy]benzaldehyde

Instead of 2,5-difluoropyridine, 2,5-dibromopyridine (13.5 g) was used and treated by the same technique as in Reference 14-1 to give the titled compound as a pale yellow oil (12.4 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.91-6.97 (m, 1H) 7.24-7.32 (m, 2H) 7.81-7.88 (m, 1H) 7.90-7.98 (m, 2H) 8.23-8.27 (m, 1H) 9.99 (s, 1H).

MS ESI/APCI Dual posi: 277 [M+H]⁺.

(2) Synthesis of the Titled Compound

A mixture of the compound (5.00 g) obtained in step (1) above, cyclopropylboronic acid (2.01 g), palladium(II) acetate (201 mg), tripotassium phosphate (13.4 g), tricyclohexylphosphine (0.6 mol/L, solution in toluene, 30.0 mL), toluene (95.0 mL) and water (5.0 mL) was stirred at 100° C. for 3 hours. After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine and thereafter the crude product was adsorbed on diatomaceous earth, with the solvents being distilled off under reduced pressure. The crude product adsorbed on the diatomaceous earth was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-63:37) to give the titled compound as a yellow oil (3.89 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.64-0.74 (m, 2H) 0.95-1.07 (m, 2H) 1.82-1.97 (m, 1H) 6.88-6.95 (m, 1H) 7.19-7.26 (m, 2H) 7.37-7.45 (m, 1H) 7.86-7.94 (m, 2H) 8.02-8.09 (m, 1H) 9.96 (s, 1H).

MS ESI/APCI Dual posi: 240 [M+H]⁺.

Reference Example 15-1 4-(2-Cyclopropylethyl)benzaldehyde

(1) Synthesis of 4-(cyclopropylethynyl)benzaldehyde

To a mixture of 4-bromobenzaldehyde (2.00 g), bis(triphenylphosphine)palladium(II) dichloride (228 mg), copper(I) iodide (20.6 mg), N,N-dimethylformamide (2.00 mL) and triethylamine (15.1 mL), cyclopropylacetylene was added and thereafter the mixture was stirred in a sealed tube at 110° C. for one minute under irradiation with microwaves. After being cooled to room temperature, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with a liquid mixture of n-hexane/ethyl acetate (1:1) three times. The combined organic layers were washed with saturated brine and dried over added anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-60:40) to give 4-(cyclopropylethynyl)benzaldehyde as a brown oil (1.79 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.80-0.99 (m, 4H) 1.42-1.54 (m, 1H) 7.46-7.54 (m, 2H) 7.75-7.82 (m, 2H) 9.98 (s, 1H).

MS ESI/APCI Dual posi: 171 [M+H]⁺.

(2) Synthesis of the Titled Compound

To a solution in ethyl acetate (22.0 mL) of the compound (1.79 g) obtained in step (1) above, 10% palladium/carbon (179 mg) was added. The mixture was stirred at room temperature for 22 hours in a hydrogen atmosphere. More of 10% palladium/carbon (179 mg) was added and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The insoluble matter was removed by filtration through Celite (registered trademark). After concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-70:30) to give the titled compound as a crude product (1.23 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.01-0.08 (m, 2H) 0.39-0.48 (m, 2H) 0.60-0.77 (m, 1H) 1.50-1.59 (m, 2H) 2.75-2.84 (m, 2H) 7.30-7.39 (m, 2H) 7.74-7.83 (m, 2H) 9.97 (s, 1H).

MS ESI/APCI Dual posi: 175 [M+H]⁺.

MS ESI/APCI Dual nega: 173 [M−H]⁻.

Reference Example 16-1 4-[(2,2-Dimethylpropoxy)methyl]benzaldehyde

(1) Synthesis of 4-(chloromethyl)-N-methoxy-N-methylbenzamide

To a solution of 4-(bromomethyl)benzoic acid (10.7 g) in chloroform (200 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.5 g), 1-hydroxybenzotriazole monohydrate (8.38 g), N,O-dimethylhydroxylamine hydrochloride (4.85 g), and triethylamine (6.94 mL) were added. After stirring the mixture at room temperature for 53 hours, chloroform (200 mL) was added. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, a saturated aqueous solution of ammonium chloride, and saturated brine successively. After passage through a phase separator, the washed mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-40:60) to give 4-(chloromethyl)-N-methoxy-N-methylbenzamide as a colorless oil (3.23 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.37 (s, 3H) 3.55 (s, 3H) 4.61 (s, 2H) 7.39-7.46 (m, 2H) 7.65-7.72 (m, 2H).

MS ESI/APCI Dual posi: 214 [M+H]⁺, 236 [M+Na]⁺.

(2) Synthesis of 4[(2,2-dimethylpropoxy)methyl]-N-methoxy-N-methylbenzamide

To a suspension of sodium hydride (60% dispersion in mineral oil, 286 mg) in N,N-dimethylformamide (23.4 mL), a solution of potassium iodide (70.2 mg) and 2,2-dimethyl-1-propanol (618 mg) in N,N-dimethylformamide (5.00 mL) were added. After stirring the mixture at room temperature for an hour, a solution in tetrahydrofuran (5.00 mL) of the compound (1.00 g) obtained in step (1) above was added. After stirring the mixture at room temperature for 3 hours, a saturated aqueous solution of ammonium chloride was added. Two extractions were conducted with a liquid mixture of n-hexane/ethyl acetate (1:1) and the combined organic layers were washed with saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-65:35) to give 4-[(2,2-dimethylpropoxy)methyl]-N-methoxy-N-methylbenzamide as a colorless oil (304 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.93-0.97 (m, 9H) 3.11-3.16 (m, 2H) 3.36 (d, J=0.3 Hz, 3H) 3.57 (s, 3H) 4.56 (s, 2H) 7.34-7.40 (m, 2H) 7.63-7.69 (m, 2H).

(3) Synthesis of the Titled Compound

To a solution in tetrahydrofuran (5.93 mL) of the compound (472 mg) obtained in step (2) above, diisobutylaluminum hydride (about 1.0 mol/L, solution in n-hexane, 2.64 mL) was added at −78° C. After stirring the mixture at −78° C. for 30 minutes, 1 mol/L hydrochloric acid (5.00 mL) was added at that temperature. After being stirred at room temperature for an hour, the reaction mixture was poured into 1 mol/L hydrochloric acid (20.0 mL). After three extractions with ethyl acetate, the combined organic layers were washed with saturated brine. The washed organic layers were passed through a phase separator and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-90:10) to give the titled compound as a colorless oil (302 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.93-0.99 (m, 9H) 3.16 (s, 2H) 4.60 (s, 2H) 7.48-7.53 (m, 2H) 7.82-7.90 (m, 2H) 10.01 (s, 1H).

Reference Example 16-2 4-{[(1-Methylcyclopropyl)methoxy]methyl}benzaldehyde

Instead of 2,2-dimethyl-1-propanol, 1-methylcyclopropanemethanol was used and treated by the same technique as in Reference Examples 16-1(2) and 16-1(3) to give the titled compound as a colorless oil.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.32-0.45 (m, 4H) 1.18 (s, 3H) 3.30 (s, 2H) 4.61 (s, 2H) 7.48-7.54 (m, 2H) 7.83-7.90 (m, 2H) 10.01 (s, 1H).

Reference Example 17-1 4-(1,1-Difluoroethyl)benzaldehyde

To a solution of 1-bromo-4-(1,1-difluoroethyl)benzene (1.00 g) in tetrahydrofuran (10.0 mL), n-butyl lithium (2.69 mol/L, solution in n-hexane, 1.68 mL) was added at −80° C. and the mixture was stirred at that temperature for 5 minutes. Subsequently, N,N-dimethylformamide (0.522 mL) was added at −80° C. and after stirring the mixture at that temperature for 20 minutes, 2 mol/L hydrochloric acid (2.50 mL) was added. After bringing the reaction mixture to room temperature, two extractions were conducted with ethyl acetate and the combined organic layers were washed with water. After drying over anhydrous magnesium sulfate and the desiccant was removed by filtration; the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-90:10) to give the titled compound as a colorless oil (510 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.95 (t, J=18.2 Hz, 3H) 7.64-7.73 (m, 2H) 7.92-7.98 (m, 2H) 10.07 (s, 1H).

MS EI posi: 170 [M]⁺.

Reference Example 18-1 4-(Difluoromethoxy)-3,5-dimethylbenzaldehyde

To a mixture of 4-hydroxy-3,5-dimethylbenzaldehyde (2.00 g), N,N-dimethylformamide (54.0 mL) and water (6.00 mL), sodium chlorodifluoroacetate (6.09 g) and potassium carbonate (3.68 g) were added and the mixture was stirred at 120° C. for 4.5 hours. After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with water four times and thereafter washed with saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was removed by filtration and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=97:3-88:12) to give the titled compound as a colorless solid (2.53 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.35-2.41 (m, 6H) 6.10-6.69 (m, 1H) 7.59-7.64 (m, 2H) 9.93 (s, 1H).

MS ESI/APCI Dual posi: 201 [M+H]⁺.

Reference Example 19-1 [3-(Trifluoromethyl)phenyl]acetaldehyde

To a solution of 3-(trifluoromethyl)phenethyl alcohol (2.00 g) in chloroform (50.0 mL), Dess-Martin periodinane (4.70 g) was added under cooling with ice. After being brought to room temperature, the reaction mixture was stirred for an hour. Subsequently, a saturated aqueous solution of sodium hydrogencarbonate (25.0 mL) and a saturated aqueous solution of sodium thiosulfate (25.0 mL) were added and the mixture was vigorously stirred for an hour. After phase separation, the organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-85:15) to give the titled compound as a pale yellow oil (1.19 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.79 (s, 2H) 7.36-7.62 (m, 4H) 9.77-9.81 (m, 1H).

MS ESI/APCI Dual nega: 187 [M−H]⁻.

Reference Example 19-2 [4-(Trifluoromethyl)phenyl]acetaldehyde

Instead of 3-(trifluoromethyl)phenethyl alcohol, 4-(trifluoromethyl)phenethyl alcohol was used and treated by the same technique as in Reference Example 19-1 to give the titled compound as a yellow oil.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.79 (s, 2H) 7.06-7.75 (m, 4H) 9.77-9.80 (m, 1H).

MS ESI/APCI Dual nega: 187 [M−H]⁻.

Reference Example 20-1 3-Cyclopropyl-4-(trifluoromethyl)benzaldehyde

(1) Synthesis of methyl-3-cyclopropyl-4-(trifluoromethyl)benzoate

Instead of 6-(4-bromophenoxy)pyridine-3-carbaldehyde, methyl 4-(trifluoromethyl)-3-{[(trifluoromethyl)sulfonyl]oxy}benzoate (see WO 2007/129745) (2.21 g) was used and treated by the same technique as in Reference Example 13-37(2) to give methyl 3-cyclopropyl-4-(trifluoromethyl)benzoate as a colorless oil (1.42 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-0.90 (m, 2H) 1.04-1.14 (m, 2H) 2.16-2.30 (m, 1H) 3.93 (s, 3H) 7.65-7.72 (m, 2H) 7.83-7.93 (m, 1H).

MS ESI/APCI Dual posi: 245 [M+H]⁺.

(2) Synthesis of [3-cyclopropyl-4-(trifluoromethyl)phenyl]methanol

To a solution in dehydrated tetrahydrofuran (50.0 mL) of the compound (1.42 g) obtained in step (1) above, lithium borohydride (380 mg) was added and the mixture was stirred at 60° C. for 4 hours. Subsequently, 1 mol/L hydrochloric acid was added under cooling with ice. Following extraction with ethyl acetate, the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate and removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-75:25) to give [3-cyclopropyl-4-(trifluoromethyl)phenyl]methanol as a colorless oil (1.18 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.72-0.83 (m, 2H) 0.97-1.10 (m, 2H) 1.70 (t, J=5.9 Hz, 1H) 2.14-2.28 (m, 1H) 4.71 (d, J=5.9 Hz, 2H) 7.04 (s, 1H) 7.23 (d, J=8.1 Hz, 1H) 7.60 (d, J=8.1 Hz, 1H).

MS ESI/APCI Dual nega: 215 [M−H]⁻.

(3) Synthesis of the Titled Compound

The compound (1.18 g) obtained in step (2) above was used as the starting material and treated by the same technique as in Reference Example 19-1 to give the titled compound as a colorless oil (760 mg).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.84-0.90 (m, 2H) 1.08-1.15 (m, 2H) 2.22-2.30 (m, 1H) 7.54 (s, 1H) 7.71-7.76 (m, 1H) 7.77-7.82 (m, 1H) 10.04 (s, 1H).

MS EI posi: 214 [M]⁺.

Reference Example 20-2 3-Methoxy-4-(trifluoromethyl)benzaldehyde

(1) Synthesis of methyl 3-methoxy-4-(trifluoromethyl)benzoate

To a solution of methyl 3-hydroxy-4-(trifluoromethyl)benzoate (see WO 2007/129745) (2.00 g) in N,N-dimethylformamide (9.00 mL), sodium hydride (60% dispersion in mineral oil, 545 mg) was added in small portions under cooling with ice. After stirring the mixture at room temperature for 30 minutes, methyl iodide (0.849 mL) was added. After stirring the reaction mixture at room temperature for 2.5 hours, iced water was added and two extractions were conducted with ethyl acetate. The combined organic layers were washed with water three times and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-85:15) to give methyl 3-methoxy-4-(trifluoromethyl)benzoate as a colorless solid (2.11 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.96 (s, 3H) 3.97 (s, 3H) 7.60-7.72 (m, 3H).

MS EI posi: 234 [M]⁺.

(2) Synthesis of the Titled Compound

The compound (2.11 g) obtained in step (1) above was used as the starting material and treated by the same techniques as in Reference Example 20-1(2) and Reference Example 19-1 to give the titled compound as a pale yellow oil (1.26 g). ¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 3.97-4.01 (m, 3H) 7.49-7.53 (m, 2H) 7.74-7.79 (m, 1H) 10.05 (s, 1H).

MS EI posi: 204 [M]⁺.

Reference Example 20-3 3-(Difluoromethoxy)-4-(trifluoromethyl)benzaldehyde

(1) Synthesis of methyl 3-(difluoromethoxy)-4-(trifluoromethyl)benzoate

A suspension of methyl 3-hydroxy-4-(trifluoromethyl)benzoate (see WO 2007/129745) (2.00 g), sodium chlorodifluoroacetate (2.08 g) and potassium carbonate (2.51 g) in N,N-dimethylformamide (30.0 mL) was stirred at 100° C. for 6 hours. After cooling the reaction mixture to room temperature, water was added to it and two extractions were conducted with ethyl acetate. The combined organic layers were washed with water three times and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-85:15) to give methyl 3-(difluoromethoxy)-4-(trifluoromethyl)benzoate as a colorless oil (1.96 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.93-4.01 (m, 3H) 6.28-6.87 (m, 1H) 7.72-7.80 (m, 1H) 7.92-8.02 (m, 2H).

MS EI posi: 270 [M]⁺.

(2) Synthesis of the Titled Compound

The compound (1.96 g) obtained in step (1) above was used as the starting material and treated by the same techniques as in Reference Example 20-1(2) and Reference Example 19-1 to give the titled compound as a colorless oil (1.35 g).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 6.50-6.79 (m, 1H) 7.79-7.86 (m, 2H) 7.88-7.91 (m, 1H) 10.07 (s, 1H).

MS EI posi: 240 [M]⁺.

Reference Example 21-1 4-Cyclobutyl-3-(trifluoromethyl)benzaldehyde

(1) Synthesis of 1[4-bromo-2-(trifluoromethyl)phenyl]cyclobutanol

To a solution of 5-bromo-2-iodobenzotrifluoride (5.00 g) in dehydrated tetrahydrofuran (140 mL), n-butyl lithium (2.69 mol/L, solution in n-hexane, 5.30 mL) was added at −78° C. and the mixture was stirred at that temperature for 25 minutes. After adding a solution of cyclobutanone (999 mg) in tetrahydrofuran (5.00 mL), the mixture was brought to room temperature and stirred for 3 days. After adding a saturated aqueous solution of ammonium chloride under cooling with ice, two extractions were conducted with ethyl acetate. The combined organic layers were washed with water and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-80:20) to give 1-[4-bromo-2-(trifluoromethyl)phenyl]cyclobutanol as a pale yellow oil (3.00 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.71-1.88 (m, 1H) 2.20-2.49 (m, 3H) 2.52-2.70 (m, 2H) 7.29-7.35 (m, 1H) 7.62-7.69 (m, 1H) 7.78-7.84 (m, 1H).

MS EI posi: 294 [M]⁺.

(2) Synthesis of 4-bromo-1-cyclobutyl-2-(trifluoromethyl)benzene

To a solution in chloroform (10.0 mL) of the compound (1.00 g) obtained in step (1) above and triethylsilane (406 mg), a solution of boron trifluoride/diethyl ether complex (601 mg) in chloroform (4.00 mL) was added at −65° C. After being brought to 0° C., the mixture was stirred at that temperature for 30 minutes. Subsequently, potassium carbonate (1.08 g) and water (10.0 mL) were added and the mixture was brought to room temperature. After phase separation, the organic layer was dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-90:10) and further purified by NH silica gel column chromatography (n-hexane) to give 4-bromo-1-cyclobutyl-2-(trifluoromethyl)benzene as a colorless oil (490 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.78-1.91 (m, 1H) 1.92-2.25 (m, 3H) 2.27-2.42 (m, 2H) 3.83 (quin, J=8.5 Hz, 1H) 7.41-7.47 (m, 1H) 7.59-7.67 (m, 1H) 7.69-7.73 (m, 1H).

MS EI posi: 278 [M]⁺.

(3) Synthesis of the Titled Compound

The compound (480 mg) obtained in step (2) above was used as the starting material and treated by the same technique as in Reference Example 17-1 to give the titled compound as a colorless oil (300 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82-1.97 (m, 1H) 1.99-2.16 (m, 1H) 2.16-2.33 (m, 2H) 2.33-2.49 (m, 2H) 3.96 (quin, J=8.6 Hz, 1H) 7.74-7.81 (m, 1H) 8.00-8.08 (m, 1H) 8.09-8.13 (m, 1H) 10.03 (s, 1H).

MS EI posi: 228 [M]⁺.

Reference Example 22-1 3-Cyclobutyl-4-(trifluoromethyl)benzaldehyde

(1) Synthesis of 1-cyclobutyl-4-nitro-2-(trifluoromethyl)benzene

A mixture of 2-iodo-5-nitrobenzotrifluoride (4.62 g), cyclobutylboronic acid (4.15 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (4.15 g), cesium carbonate (22.6 g), toluene (67.0 mL) and water (33.0 mL) was stirred in a sealed tube at 80° C. for 6 hours. After cooling the reaction mixture to room temperature, extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-94:6) to give 1-cyclobutyl-4-nitro-2-(trifluoromethyl)benzene as a pale yellow oil (1.69 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.84-1.99 (m, 1H) 2.00-2.33 (m, 3H) 2.35-2.52 (m, 2H) 3.89-4.05 (m, 1H) 7.74-7.81 (m, 1H) 8.34-8.43 (m, 1H) 8.45-8.50 (m, 1H).

MS ESI/APCI Dual nega: 244 [M−H]⁻.

(2) Synthesis of 4-cyclobutyl-3-(trifluoromethyl)aniline

A mixture of the compound (1.69 g) obtained in step (1) above, an iron powder (2.14 g), ammonium chloride (442 mg), ethanol (26.0 mL) and water (13.0 mL) was stirred at 85° C. for an hour. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark). To the filtrate, a saturated aqueous solution of sodium hydrogencarbonate was added and three extractions were conducted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-75:25) to give 4-cyclobutyl-3-(trifluoromethyl)aniline as a pale yellow oil (1.34 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.72-1.87 (m, 1H) 1.87-2.21 (m, 3H) 2.21-2.36 (m, 2H) 3.66-3.85 (m, 3H) 6.78-6.86 (m, 1H) 6.88-6.93 (m, 1H) 7.31-7.37 (m, 1H).

MS ESI posi: 216 [M+H]⁺.

(3) Synthesis of 4-cyclobutyl-2-iodo-5-(trifluoromethyl)aniline

To a mixture of the compound (1.34 g) obtained in step (2) above, sodium hydrogencarbonate (628 mg), chloroform (32.0 mL) and methanol (8.00 mL), a solution of iodine monochloride (1.21 g) in chloroform (8.00 mL) was added dropwise at room temperature over a period of 30 minutes. The resulting mixture was stirred at room temperature for two hours. After adding a solution of 25% sodium metabisulfite in water (20.0 g) under cooling with ice, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with chloroform and the combined organic layers were dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give 4-cyclobutyl-2-iodo-5-(trifluoromethyl)aniline as a brown oil (2.08 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.71-1.89 (m, 1H) 1.90-2.20 (m, 3H) 2.20-2.37 (m, 2H) 3.60-3.78 (m, 1H) 4.12 (br. s, 2H) 6.92 (s, 1H) 7.76 (s, 1H).

MS ESI posi: 342 [M+H]⁺.

(4) Synthesis of 2-cyclobutyl-4-iodo-1-(trifluoromethyl)benzene

To a suspension in acetonitrile (60.0 mL) of the compound (2.08 g) obtained in step (3) above and sodium nitrite (2.10 g), conc. sulfuric acid (6.00 mL) was added at 0° C. over a period of 15 minutes. After stirring the mixture at that temperature for an hour, ethanol (24.0 mL) was added. After being stirred at 100° C. for two hours, the reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into iced water and two extractions were conducted with chloroform. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure and the residue was purified twice by NH silica gel column chromatography (with n-hexane only) to give 2-cyclobutyl-4-iodo-1-(trifluoromethyl)benzene as a colorless oil (1.25 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.77-1.93 (m, 1H) 1.95-2.26 (m, 3H) 2.27-2.40 (m, 2H) 3.81 (quin, J=8.8 Hz, 1H) 7.26-7.31 (m, 1H) 7.60-7.67 (m, 1H) 7.88 (s, 1H).

(5) Synthesis of the Titled Compound

The compound (1.25 g) obtained in step (4) above was used as the starting material and treated by the same technique as in Reference Example 17-1 to give the titled compound as a colorless oil (660 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82-2.17 (m, 2H) 2.17-2.49 (m, 4H) 3.86-4.02 (m, 1H) 7.73-7.83 (m, 2H) 8.09 (s, 1H) 10.11 (s, 1H).

MS EI posi: 228 [M]⁺.

Reference Example 23-1 cis-2-Phenylcyclopropanecarbaldehyde

(1) Synthesis of ethyl trans-2-phenylcyclopropanecarboxylate and ethyl cis-2-phenylcyclopropanecarboxylate

To a suspension of styrene (3.00 g) and rhodium(II) acetate dimer (40.0 mg) in 1,2-dichloroethane (29.0 mL), a solution of ethyl diazoacetate (3.03 mL) in 1,2-dichloroethane (29.0 mL) was added over a period of 4 hours and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane:diethyl ether=20:1) to give ethyl trans-2-phenylcyclopropanecarboxylate as a colorless oil (2.42 g) and ethyl cis-2-phenylcyclopropanecarboxylate as a colorless oil (1.51 g).

Ethyl trans-2-phenylcyclopropanecarboxylate

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24-1.36 (m, 4H) 1.54-1.64 (m, 1H) 1.86-1.95 (m, 1H) 2.47-2.58 (m, 1H) 4.17 (q, J=7.1 Hz, 2H) 7.06-7.13 (m, 2H) 7.16-7.32 (m, 3H).

MS ESI/APCI Dual posi: 191 [M+H]⁺, 213 [M+Na]⁺.

Ethyl cis-2-phenylcyclopropanecarboxylate

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97 (t, J=7.1 Hz, 3H) 1.28-1.37 (m, 1H) 1.66-1.76 (m, 1H) 2.02-2.14 (m, 1H) 2.51-2.66 (m, 1H) 3.87 (q, J=7.1 Hz, 2H) 7.14-7.31 (m, 5H).

MS ESI/APCI Dual posi: 191 [M+H]⁺, 213 [M+Na]⁺.

(2) Synthesis of (cis-2-phenylcyclopropyl)methanol

To a solution in diethyl ether (12.0 mL) of the ethyl cis-2-phenylcyclopropanecarboxylate (1.51 g) obtained in step (1) above, a suspension of aluminum lithium hydride (393 mg) in diethyl ether (12.0 mL) was added at 0° C. After being brought to room temperature, the mixture was stirred for 2 hours. After adding sodium sulfate decahydrate at 0° C., the reaction mixture was brought to room temperature and stirred for an hour. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure to give (cis-2-phenylcyclopropyl)methanol as a colorless oil (1.21 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.84-0.94 (m, 1H) 0.99-1.11 (m, 1H) 1.42-1.58 (m, 1H) 2.20-2.38 (m, 1H) 3.18-3.34 (m, 1H) 3.41-3.55 (m, 1H) 7.11-7.35 (m, 5H).

MS ESI/APCI Dual posi: 171 [M+Na]⁺.

(3) Synthesis of the Titled Compound

The compound (1.21 g) obtained in step (2) above was used as the starting material and treated by the same technique as in Reference Example 19-1 to give the titled compound as a pale yellow oil (1.08 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.53-1.65 (m, 1H) 1.84-1.94 (m, 1H) 2.08-2.20 (m, 1H) 2.78-2.89 (m, 1H) 7.19-7.37 (m, 5H) 8.63-8.71 (m, 1H).

MS ESI/APCI Dual posi: 147 [M+H]⁺, 169 [M+Na]⁺.

Reference Example 23-2 trans-2-Phenylcyclopropanecarbaldehyde

The ethyl trans-2-phenylcyclopropanecarboxylate (1.00 g) obtained in Reference Example 23-1(1) was used as the starting material and treated by the same techniques as in Reference Example 23-1(2) and Reference Example 19-1 to give a roughly purified product (620 mg) containing the titled compound.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49-1.59 (m, 1H) 1.70-1.78 (m, 1H) 2.13-2.23 (m, 1H) 2.59-2.68 (m, 1H) 7.08-7.16 (m, 2H) 7.18-7.34 (m, 3H) 9.30-9.35 (m, 1H).

MS ESI/APCI Dual posi: 147 [M+H]⁺.

Reference Example 23-3 2-(4-Fluorophenyl)cyclopropanecarbaldehyde

Instead of styrene, 4-fluorostyrene (10.0 g) was used and treated by the same techniques as in Reference Example 23-1(1) and (2) as well as Reference Example 19-1 to give the titled compound as a colorless oil (4.48 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31-1.55 (m, 1H) 1.59-1.78 (m, 1H) 1.80-2.19 (m, 1H) 2.53-2.68 (m, 1H) 6.91-7.16 (m, 4H) 9.34 (d, J=4.5 Hz, 1H).

MS ESI/APCI Dual posi: 165 [M+H]⁺.

Reference Example 24-1 and Reference Example 24-2 trans-3-Phenylcyclobutanecarbaldehyde (Reference Example 24-1) and cis-3-Phenylcyclobutanecarbaldehyde (Reference Example 24-2)

To a solution of diethyl isocyanomethylphosphonate (1.47 g) in tetrahydrofuran (45.0 mL), n-butyl lithium (2.69 mol/L, solution in n-hexane, 2.99 mL) was added at −78° C. and thereafter the mixture was stirred at that temperature for 80 minutes. After adding a solution of 3-phenylcyclobutanone (1.03 g) in tetrahydrofuran (15.0 mL) at −78° C. over a period of 30 minutes, the mixture was stirred at room temperature for 4 hours. After adding cone. hydrochloric acid (12.0 mL) at room temperature, the mixture was stirred at that temperature for 18 hours. Water was added to the reaction mixture which was then extracted with ethyl acetate twice. The combined organic layers were washed with saturated brine and thereafter dried over anhydrous magnesium sulfate. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-96:4) to give the titled compound of Reference Example 24-1 as a colorless oil (160 mg) and the titled compound of Reference Example 24-2 as a colorless oil (390 mg).

trans-3-Phenylcyclobutanecarbaldehyde (Reference Example 24-1)

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.30-2.58 (m, 2H) 2.65-2.83 (m, 2H) 3.08-3.28 (m, 1H) 3.47-3.68 (m, 1H) 7.17-7.38 (m, 5H) 9.94-9.97 (m, 1H).

cis-3-Phenylcyclobutanecarbaldehyde (Reference Example 24-2)

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.30-2.49 (m, 2H) 2.51-2.65 (m, 2H) 3.13-3.29 (m, 1H) 3.53-3.68 (m, 1H) 7.17-7.37 (m, 5H) 9.71-9.75 (m, 1H).

Reference Example 24-3 trans-3-(4-Fluorophenyl)cyclobutanecarbaldehyde

Instead of 3-phenylcyclobutanone, 3-(4-fluorophenyl)cyclobutanone (4.63 g) was used and treated by the same technique as in Reference Example 24-1 to give the titled compound as a colorless oil (720 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.26-2.45 (m, 2H) 2.63-2.81 (m, 2H) 3.09-3.24 (m, 1H) 3.47-3.65 (m, 1H) 6.94-7.07 (m, 2H) 7.12-7.23 (m, 2H) 9.95 (d, J=1.7 Hz, 1H).

MS ESI/APCI Dual nega: 177 [M−H]⁻.

Reference Example 25-1 4-Benzylcyclohexanone

(1) Synthesis of 9-benzyl-3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-ol

To a solution of 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal (3.76 g) and zinc chloride (about 1.0 mol/L, solution in diethyl ether, 1.90 mL) in tetrahydrofuran (63.0 mL), benzylmagnesium bromide (about 1.0 mol/L, solution in tetrahydrofuran, 24.7 mL) was added at 0° C. and thereafter the mixture was stirred at that temperature for 2.5 hours. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added and three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine and thereafter dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-60:40) to give 9-benzyl-3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-ol as a colorless solid (1.28 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97 (s, 6H) 1.43-1.89 (m, 6H) 1.95-2.13 (m, 2H) 2.76 (s, 2H) 3.41-3.58 (m, 4H) 7.16-7.36 (m, 5H).

MS ESI/APCI Dual posi: 313 [M+Na]⁺.

(2) Synthesis of the Titled Compound

To a solution in toluene (44.0 mL) of the compound (1.28 g) obtained in step (1) above, p-toluenesulfonic acid monohydrate (84.0 mg) was added and thereafter the mixture was refluxed for 3 hours with a Dean-Stark apparatus. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50). A suspension of the resulting purified product (935 mg) and 20% palladium hydroxide/carbon (93.5 mg) in methanol (11.3 mL) was stirred at room temperature for 5 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure. To a solution of the resulting residue (938 mg) in tetrahydrofuran (34.3 mL), 1 mol/L hydrochloric acid (9.30 mL) was added at 0° C. and the mixture was stirred at room temperature for 14.5 hours. After concentrating the stirred mixture under reduced pressure, three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine. After passage through a phase separator, the washed organic layers were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-50:50) to give the titled compound as a colorless oil (225 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36-1.52 (m, 2H) 1.95-2.10 (m, 3H) 2.22-2.45 (m, 4H) 2.62 (d, J=6.7 Hz, 2H) 7.10-7.36 (m, 5H).

MS ESI/APCI Dual posi: 189 [M+H]⁺, 211 [M+Na]⁺.

Reference Example 26-1 1-(Biphenyl-4-yl)propan-1-one

(1) Synthesis of 1-(biphenyl-4-yl)propan-1-ol

To a solution of 4-phenylbenzaldehyde (1.20 g) in diethyl ether (13.2 mL), ethylmagnesium bromide (about 3.0 mol/L, solution in diethyl ether, 3.29 mL) was added at 0° C. After stirring the mixture at room temperature for 3 hours, the precipitate was recovered by filtration. After dissolving the recovered precipitate in a liquid mixture of ethyl acetate and a saturated aqueous solution of ammonium chloride, three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine. After passage through a phase separator, the washed organic layers were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-70:30) to give 1-(biphenyl-4-yl)propan-1-ol as a colorless solid (1.27 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.96 (t, J=7.4 Hz, 3H) 1.72-1.98 (m, 2H) 4.59-4.71 (m, 1H) 7.29-7.48 (m, 5H) 7.54-7.63 (m, 4H).

MS EI posi: 212 [M]⁺.

(2) Synthesis of the Titled Compound

To a solution in diethyl ether (30.0 mL) of the compound (1.27 g) obtained in step (1) above, manganese(IV) oxide (9.57 g) was added and the mixture was stirred at room temperature for 45 hours. After removing the insoluble matter by filtration, the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in acetone (60.0 mL), a Jones' reagent {see Org. Synth., Coll. Vol. VI, 542 (1988)}(1.20 mL) was added until the color of the Jones' reagent was yet to disappear. The reaction mixture was concentrated under reduced pressure and ethyl acetate and water were added to the residue. Extraction with ethyl acetate was conducted three times and the combined organic layers were washed with saturated brine. After passage through a phase separator, the washed organic layers were concentrated under reduced pressure. The resulting residue was recrystallized with n-hexane to give the titled compound as a colorless solid (921 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J=7.3 Hz, 3H) 3.04 (q, J=7.3 Hz, 2H) 7.34-7.52 (m, 3H) 7.58-7.73 (m, 4H) 8.00-8.09 (m, 2H).

MS ESI/APCI Dual posi: 211 [M+H]⁺, 233 [M+Na]⁺.

Reference Example 27-1 1-(Biphenyl-4-yl)cyclopropaneamine

The compound 4-cyanobiphenyl (2.83 g) was used as the starting material and treated by the same technique as in Reference Example 4-1(2) to give the titled compound as a pale yellow solid (1.06 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.99-1.07 (m, 2H) 1.08-1.15 (m, 2H) 7.28-7.49 (m, 5H) 7.51-7.62 (m, 4H).

MS ESI/APCI Dual posi: 210 [M+H]⁺.

Reference Example 27-2 1-[4-(Trifluoromethyl)phenyl]cyclopropaneamine

The compound 4-(trifluoromethyl)benzonitrile (5.18 g) was used as the starting material and treated by the same technique as in Reference Example 4-1(2) to give the titled compound as a pale yellow solid (2.92 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.00-1.07 (m, 2H) 1.11-1.19 (m, 2H) 7.31-7.45 (m, 2H) 7.49-7.64 (m, 2H).

MS ESI/APCI Dual posi: 202 [M+H]⁺.

Reference Example 27-3 2-[4-(Trifluoromethyl)phenyl]propane-2-amine

To a solution of 4-(trifluoromethyl)benzonitrile (3.01 g) in diethyl ether (88.0 mL), methylmagnesium bromide (about 3.0 mol/L, solution in diethyl ether, 17.6 mL) was added and the mixture was stirred at room temperature for 40 minutes. To the reaction mixture, tetraisopropyl orthotitanate (5.15 mL) was added slowly and thereafter the mixture was refluxed for 6 hours. After cooling the mixture to 0° C., an aqueous solution of 20% sodium hydroxide was added and the mixture was stirred at room temperature for an hour. After phase separation, the aqueous layer was extracted with diethyl ether twice. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure. The resulting residue was dissolved in 5% hydrochloric acid and washed with diethyl ether twice. The aqueous layer was rendered basic with an aqueous solution of 20% sodium hydroxide and extracted with diethyl ether three times. The combined organic layers were washed with saturated brine and thereafter passed through a phase separator to be concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-10:90) to give the titled compound as a yellow oil (1.81 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 6H) 7.54-7.69 (m, 4H).

MS ESI/APCI Dual posi: 204 [M+H]⁺.

Reference Example 28-1 Methyl (3S)-3-amino-4-methoxybutanoate hydrochloride

(1) Synthesis of tert-butyl [(2S)-1-cyano-3-hydroxypropan-2-yl]carbamate

To a solution of N-α-(tert-butoxycarbonyl)-β-cyano-L-alanine (1.00 g) in tetrahydrofuran (13 mL), isobutyl chloroformate (674 μL) and triethylamine (716 μL) were added successively at 0° C. and the mixture was stirred at that temperature for 2 hours. After removing the precipitate by filtration, the filtrate was concentrated under reduced pressure. To a mixture of the resulting residue, tetrahydrofuran (13 mL) and water (4 mL), sodium borohydride (530 mg) were added and the mixture was stirred at room temperature for 30 minutes. After adding water, extraction was conducted with ethyl acetate. The combined organic layers were washed with saturated brine and thereafter passed through a phase separator to be concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=80:20-40:60) to give tert-butyl [(2S)-1-cyano-3-hydroxypropan-2-yl]carbamate as a colorless oil (650 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9H) 2.10-2.18 (m, 1H) 2.63-2.78 (m, 2H) 3.69-3.88 (m, 2H) 3.89-4.03 (m, 1H) 5.02 (br. s., 1H).

MS ESI/APCI Dual posi: 223 [M+Na]⁺.

(2) Synthesis of tert-butyl [(2S)-1-cyano-3-methoxypropan-2-yl]carbamate

To a solution in tetrahydrofuran (10 mL) of the compound (650 mg) obtained in step (1) above, sodium hydride (60% dispersion in mineral oil, 143 mg) was added under cooling with ice. After stirring the mixture at the same temperature for 10 minutes, methyl iodide (603 μL) was added. After stirring the mixture at the same temperature for 30 minutes and then at room temperature for an hour, water was added and extraction was conducted with ethyl acetate. The combined organic layers were passed through a phase separator and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-60:40) to give tert-butyl [(2S)-1-cyano-3-methoxypropan-2-yl]carbamate as a colorless oil (247 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 2.69 (d, J=6.2 Hz, 2H) 3.39 (s, 3H) 3.41-3.49 (m, 1H) 3.53-3.61 (m, 1H) 4.02 (br. s., 1H) 4.96 (br. s., 1H).

MS ESI/APCI Dual posi: 237 [M+Na]⁺.

MS ESI/APCI Dual nega: 213 [M−H]⁻.

(3) Synthesis of the Titled Compound

To a solution in 1,4-dioxane (2.0 mL) of the compound (247 mg) obtained in step (2) above, conc. hydrochloric acid (3.0 mL) was added and the mixture was stirred at 100° C. for an hour. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was used as the starting material and treated by the same technique as in Reference Example 3-4 to give the titled compound as a colorless solid (247 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.60-2.84 (m, 2H) 3.30 (s, 3H) 3.44-3.59 (m, 3H) 3.64 (s, 3H).

MS ESI/APCI Dual posi: 148 [M+H]⁺.

Reference Example 28-2 Methyl (3 S)-3-amino-4-(dimethylamino)butanoate hydrochloride

(1) Synthesis of (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyanopropyl 4-methylbenzenesulfonate

To a solution in chloroform (20 mL) of the compound (820 mg) obtained in Reference Example 28-1(1), p-toluenesulfonyl chloride (1.56 g) and triethylamine (1.14 mL) were added and the mixture was stirred at room temperature for 3 hours. After adding more p-toluenesulfonyl chloride (1.56 g) and triethylamine (1.14 mL), the mixture was stirred at room temperature for 30 minutes. Subsequently, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with chloroform. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=80:20-40:60) to give (2S)-2-[(tert-butoxycarbonyl)amino]-3-cyanopropyl 4-methylbenzenesulfonate as a colorless solid (1.32 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9H) 2.47 (s, 3H) 2.63-2.71 (m, 2H) 4.02-4.21 (m, 3H) 4.86-5.01 (m, 1H) 7.39 (d, J=8.5 Hz, 2H) 7.81 (d, J=8.5 Hz, 2H).

MS ESI/APCI Dual posi: 377 [M+Na]⁺.

(2) Synthesis of tert-butyl [(2S)-1-cyano-3-(dimethylamino)propan-2-yl]carbamate

To a solution in ethanol (20 mL) of the compound (1.32 g) obtained in step (1) above, dimethylamine (about 50%, aqueous solution, 3.92 mL) and triethylamine (5194) were added and the mixture was stirred at 80° C. for an hour. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the resulting residue, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with ethyl acetate. The combined organic layers were washed with saturated brine and after passage through a phase separator, they were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=99:1-95:5) to give tert-butyl [(2S)-1-cyano-3-(dimethylamino)propan-2-yl]carbamate as a pale yellow oil (340 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 2.25 (s, 6H) 2.31-2.55 (m, 2H) 2.62-2.76 (m, 1H) 2.78-2.91 (m, 1H) 3.74-3.90 (m, 1H) 4.99 (br. s., 1H).

MS ESI/APCI Dual posi: 228 [M+H]⁺, 250 [M+Na]⁺.

MS ESI/APCI Dual nega: 226 [M−H]⁻.

(3) Synthesis of the Titled Compound

The compound (340 mg) obtained in step (2) above was used as the starting material and treated by the same technique as in Reference Example 28-1(3) to give the titled compound. Note that the titled compound was used in a subsequent reaction as it remained a crude product.

Reference Example 29-1 Methyl (3-amino-5-oxopyrrolidin-3-yl)acetate

(1) Synthesis of 2-tert-butyl 1,3-dimethyl 2-cyanopropane-1,2,3-tricarboxylate

To a solution of tert-butyl cyanoacetate (10.0 g) in toluene (100 mL), sodium hydride (60% dispersion in mineral oil, 2.83 g) was added under cooling with ice. After being stirred at 80° C. for an hour, the mixture was cooled to 50° C. and methyl bromoacetate (6.51 mL) was added slowly. After adding tetrahydrofuran (15 mL), the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled with ice and then sodium hydride (60% dispersion in mineral oil, 2.83 g) was added. After being stirred at 80° C. for an hour, the mixture was cooled to 50° C. and then methyl bromoacetate (6.51 mL) was added slowly. Subsequently, tetrahydrofuran (15 mL) was added and the mixture was stirred at 80° C. for two hours. After the reaction mixture to room temperature, a saturated aqueous solution of ammonium chloride and water were added and extraction was conducted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated brine successively and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-40:60) to give 2-tert-butyl 1,3-dimethyl 2-cyanopropane-1,2,3-tricarboxylate as a pale yellow oil (17.8 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9H) 2.96-3.12 (m, 4H) 3.74 (s, 6H).

MS ESI/APCI Dual posi: 286 [M+H]⁺, 308 [M+Na]⁺.

(2) Synthesis of tert-butyl 3-(2-methoxy-2-oxoethyl)-5-oxopyrrolidine-3-carboxylate

To a solution in methanol (70 mL) of the compound (5.00 g) obtained in step (1) above, a Raney nickel catalyst (about 7.5 g) was added. The mixture was stirred at 70° C. for 8 hours in a hydrogen atmosphere with 0.4 megapascals (MPa). After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. To the resulting residue, diethyl ether (50 mL) and hexane (10 mL) were added and the mixture was stirred at room temperature for 15 minutes. The resulting precipitate was recovered by filtration to give tert-butyl 3-(2-methoxy-2-oxoethyl)-5-oxopyrrolidine-3-carboxylate as a colorless solid (1.75 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9H) 2.33 (d, J=17.4 Hz, 1H) 2.79-2.90 (m, 3H) 3.35 (dd, J=10.3, 0.8 Hz, 1H) 3.69 (s, 3H) 3.84 (dd, J=10.3, 0.8 Hz, 1H) 5.73 (br. s., 1H).

MS ESI/APCI Dual posi: 258 [M+H]⁺, 280 [M+Na]⁺.

(3) Synthesis of methyl (3-{[(benzyloxy)carbonyl]amino}-5-oxopyrrolidin-3-yl)acetate

To the compound (3.41 g) obtained in step (2) above, trifluoroacetic acid (30 mL) was added and the mixture was stirred at room temperature for 4 hours. After concentrating under reduced pressure, chloroform was added to the resulting residue, which was concentrated again under reduced pressure. To a solution of the resulting residue in benzene (50 mL), there were successively added tetrahydrofuran (12 mL), triethylamine (3.71 mL), diphenylphosphoryl azide (3.73 mL) and benzyl alcohol (1.79 mL) and the mixture was stirred for 4 hours under reflux with heating. After cooling the reaction mixture to room temperature, ethyl acetate was added to it, which was then washed with water, an aqueous solution of 10% citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and saturated brine successively and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-85:15) to give methyl (3-{[(benzyloxy)carbonyl]amino}-5-oxopyrrolidin-3-yl)acetate as a colorless gum (1.91 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.57 (d, J=17.2 Hz, 1H) 2.78 (d, J=17.2 Hz, 1H) 2.91 (d, J=16.2 Hz, 1H) 3.01 (d, J=16.2 Hz, 1H) 3.51 (dd, J=10.6, 0.8 Hz, 1H) 3.67 (s, 3H) 3.70-3.81 (m, 1H) 5.08 (s, 2H) 5.46 (br. s., 1H) 5.69 (br. s., 1H) 7.27-7.42 (m, 5H).

MS ESI/APCI Dual posi: 307 [M+H]⁺, 329 [M+Na]⁺.

MS ESI/APCI Dual nega: 341 [M+Cl]⁻.

(4) Synthesis of the Titled Compound

To a solution in methanol (30 mL) of the compound (1.91 g) obtained in step (3) above, 20% palladium hydroxide/carbon (191 mg) was added and the mixture was stirred at room temperature for an hour in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give the titled compound as a colorless oil (1.12 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.32 (d, J=16.7 Hz, 1H) 2.47 (d, J=16.7 Hz, 1H) 2.61-2.75 (m, 2H) 3.33 (d, J=10.2 Hz, 1H) 3.46 (d, J=10.2 Hz, 1H) 3.72 (s, 3H) 5.72 (br. s., 1H).

MS ESI/APCI Dual posi: 173 [M+H]⁺.

Reference Example 29-2 Methyl (3-amino-1-methyl-5-oxopyrrolidin-3-yl)acetate

(1) Synthesis of tert-butyl 3-(2-methoxy-2-oxoethyl)-1-methyl-5-oxopyrrolidine-3-carboxylate

The compound (4.0 g) obtained in Reference Example 29-1(2) was used as the starting material and treated by the same technique as in Reference Example 28-1(2) to give tert-butyl 3-(2-methoxy-2-oxoethyl)-1-methyl-5-oxopyrrolidine-3-carboxylate as a pale yellow oil (3.74 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 2.39 (d, J=17.3 Hz, 1H) 2.70 (d, J=16.6 Hz, 1H) 2.79-2.90 (m, 5H) 3.32 (d, J=10.6 Hz, 1H) 3.69 (s, 3H) 3.86 (d, J=10.6 Hz, 1H).

MS ESI/APCI Dual posi: 272 [M+H]⁺.

(2) Synthesis of the Titled Compound

The compound (3.74 g) obtained in step (1) above was used as the starting material and treated by the same techniques as in Reference Example 29-1(3) and (4) to give the titled compound.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.36-2.45 (m, 1H) 2.47-2.56 (m, 1H) 2.59-2.72 (m, 2H) 2.85-2.89 (m, 3H) 3.33 (d, J=10.4 Hz, 1H) 3.47 (d, J=10.4 Hz, 1H) 3.72 (s, 3H).

MS ESI/APCI Dual posi: 187 [M+H]⁺. 209 [M+Na]⁺.

Reference Example 30-1 Methyl L-α-asparaginate

To a solution of N-α-(9-fluorenylmethoxycarbonyl)-L-aspartic α-amide (744 mg) in tetrahydrofuran (8 mL), trimethylsilyldiazomethane (2.0 mol/L, solution in diethyl ether, 1.20 mL) and methanol (808 μL) were added under cooling with ice. After being brought to room temperature, the mixture was stirred for 2.5 hours. The reaction mixture was then concentrated under reduced pressure. To a solution of the resulting residue in acetonitrile (14 mL), diethylamine (621 μL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and to the resulting residue, diethyl ether was added and the mixture was stirred. The resulting precipitate was recovered by filtration to give the titled compound as a colorless solid (274 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.37 (dd, J=15.6, 8.2 Hz, 1H) 2.62 (dd, J=15.6, 5.1 Hz, 1H) 3.46 (dd, J=8.2, 5.1 Hz, 1H) 3.58 (s, 3H).

MS ESI/APCI Dual posi: 169 [M+Na]⁺.

Reference Example 30-2 Methyl D-α-asparaginate

Instead of N-α-(9-fluorenylmethoxycarbonyl)-L-aspartic α-amide, N-α-(9-fluorenylmethoxycarbonyl)-D-aspartic α-amide was used and treated by the same technique as in Reference Example 30-1 to give the titled compound as a colorless oil. Note that the titled compound was used in a subsequent reaction as it remained a crude product.

Reference Example 31-1 6-[(1-Methylcyclopropyl)methoxy]pyridine-3-carbaldehyde

(1) Synthesis of 6-chloro-N-methoxy-N-methylpyridine-3-carboxamide

Instead of 4-(bromomethyl)benzoic acid, 6-chloronicotinic acid (6.50 g) was used and treated by the same technique as in Reference Example 16-1(1) to give 6-chloro-N-methoxy-N-methylpyridine-3-carboxamide as a colorless oil (7.55 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.39 (s, 3H) 3.56 (s, 3H) 7.39 (dd, J=8.3, 0.7 Hz, 1H) 8.03 (dd, J=8.3, 2.3 Hz, 1H) 8.78 (dd, J=2.3, 0.7 Hz, 1H).

MS ESI/APCI Dual posi: 201 [M+H]⁺.

(2) Synthesis of N-methoxy-N-methyl-6-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxamide

To a solution of potassium tert-butoxide (1.68 g) in tetrahydrofuran (30 mL), a solution of 1-methylcyclopropanemethanol (1.29 g) in tetrahydrofuran (5 mL) was added and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture was cooled to 0° C., a solution in tetrahydrofuran (5 mL) of the compound (3.00 g) obtained in step (1) above was added and after being brought to room temperature, the reaction mixture was stirred for an hour. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-50:50) to give N-methoxy-N-methyl-6-[(1-methylcyclopropyl)methoxy]pyridine-3-carboxamide as a colorless oil (2.02 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.38-0.47 (m, 2H) 0.52-0.60 (m, 2H) 1.23 (s, 3H) 3.37 (s, 3H) 3.58 (s, 3H) 4.15 (s, 2H) 6.73-6.84 (m, 1H) 8.00 (dd, J=8.7, 2.3 Hz, 1H) 8.60 (dd, J=2.3, 0.7 Hz, 1H).

MS ESI/APCI Dual posi: 251 [M+H]⁺.

(3) Synthesis of the Titled Compound

The compound (2.00 g) obtained in step (2) above was used and treated by the same technique as in Reference Example 16-1(3) to give the titled compound as a colorless oil (1.51 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.39-0.48 (m, 2H) 0.53-0.62 (m, 2H) 1.23 (s, 3H) 4.20 (s, 2H) 6.83-6.92 (m, 1H) 8.02-8.11 (m, 1H) 8.52-8.63 (m, 1H) 9.91-9.97 (m, 1H).

MS ESI/APCI Dual posi: 192 [M+H]⁺.

Reference Example 31-2 6-(2-Cyclopropylethoxyl)pyridine-3-carbaldehyde

Instead of 1-methylcyclopropanemethanol, 2-cyclopropylethanol (1.29 g) was used and treated by the same technique as in Reference Example 31-1 to give the titled compound as a colorless oil (1.25 g). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.08-0.18 (m, 2H) 0.42-0.54 (m, 2H) 0.75-0.89 (m, 1H) 1.63-1.75 (m, 2H) 4.48 (t, J=6.8 Hz, 2H) 6.77-6.88 (m, 1H) 8.01-8.10 (m, 1H) 8.58-8.67 (m, 1H) 9.92-9.98 (m, 1H).

MS ESI/APCI Dual posi: 192 [M+H]⁺.

Reference Example 32-1 trans-4-(4-Chlorophenoxyl)cyclohexanecarbaldehyde

(1) Synthesis of cis-4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide

Instead of 4-(bromomethyl)benzoic acid, cis-4-hydroxycyclohexanecarboxylic acid (1.45 g) was used and treated by the same technique as in Reference Example 16-1(1) to give cis-4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide as a yellow oil (0.87 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49-1.74 (m, 4H) 1.79-2.02 (m, 4H) 2.65-2.79 (m, 1H) 3.19 (s, 3H) 3.70 (s, 3H) 3.99-4.08 (m, 1H).

MS ESI/APCI Dual posi: 188 [M+H]⁺.

(2) Synthesis of trans-4-(4-chlorophenoxy)-N-methoxy-N-methylcyclohexanecarboxamide

Instead of 2-cyclopropylethanol and 4-hydroxybenzaldehyde, the compound (850 mg) obtained in step (1) above and p-chlorophenol (700 mg) were respectively used and treated by the same technique as in Reference Example 11-1 to give trans-4-(4-chlorophenoxy)-N-methoxy-N-methylcyclohexanecarboxamide as a colorless solid (458 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37-1.75 (m, 4H) 1.86-1.98 (m, 2H) 2.16-2.29 (m, 2H) 2.65-2.79 (m, 1H) 3.19 (s, 3H) 3.72 (s, 3H) 4.06-4.26 (m, 1H) 6.78-6.88 (m, 2H) 7.18-7.25 (m, 2H).

MS ESI/APCI Dual posi: 298 [M+H]⁺.

(3) Synthesis of the Titled Compound

The compound (455 mg) obtained in step (2) above was used and treated by the same technique as in Reference Example 23-1(2) to give the titled compound as a pale yellow solid (379 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.38-1.64 (m, 4H) 2.01-2.21 (m, 4H) 2.25-2.39 (m, 1H) 4.03-4.27 (m, 1H) 6.78-6.87 (m, 2H) 7.18-7.26 (m, 2H) 9.66-9.72 (m, 1H).

MS ESI/APCI Dual nega: 237 [M−H]⁻.

In the following Reference Examples 32-2 to 32-9, a commercial grade of the corresponding phenols and a commercial grade of the corresponding alcohols were used and treated by the method described in Reference Example 32-1 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 11-1.

TABLE 11-1 Compound Salt No. Structure Analytical Data information Reference Example 32-2

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.37-1.64 (m, 4 H) 2.02-2.21 (m, 4 H) 2.24-2.37 (m, 4 H) 4.06-4.24 (m, 1 H) 6.75-6.84 (m, 2 H) 7.02-7.12 (m, 2 H) 9.65-9.71 (m, 1H). Reference Example 32-3

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.21 (t, J = 7.6 Hz, 3 H) 1.34-1.64 (m, 4 H) 2.00-2.39 (m, 5 H) 2.59 (q, J = 7.6 Hz, 2 H) 4.08-4.24 (m, 1 H) 6.73-6.89 (m, 2 H) 7.05-7.15 (m, 2 H) 9.63-9.74 (m, 1 H). Reference Example 32-4

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.34-1.66 (m, 4 H) 1.84-2.39 (m, 5 H) 4.84-5.03 (m, 1 H) 6.57-6.69 (m, 1 H) 7.43-7.55 (m, 1 H) 8.03-8.10 (m, 1 H) 9.62-9.72 (m, 1 H). Reference Example 32-5

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.34-1.76 (m, 4 H) 1.99-2.37 (m, 5 H) 4.92-5.09 (m, 1 H) 6.63-6.73 (m, 1 H) 6.79-6.89 (m, 1 H) 7.49-7.61 (m, 1 H) 8.08-8.17 (m, 1 H) 9.64-9.74 (m, 1 H). MS ESI/APCI Dual posi: 206[M + H]⁺. Reference Example 32-6

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.56-0.66 (m, 2 H) 0.83-0.95 (m, 2 H) 1.35-1.67 (m, 4 H) 1.76-1.91 (m, 1 H) 2.03-2.38 (m, 5 H) 4.04-4.28 (m, 1 H) 6.76-6.84 (m, 2 H) 6.96-7.03 (m, 2 H) 9.66-9.72 (m, 1 H). Reference Example 32-7

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.52-0.69 (m, 2 H) 0.84-1.01 (m, 2 H) 1.33-1.65 (m, 4 H) 1.72-1.92 (m, 1 H) 1.99-2.36 (m, 5 H) 4.82-5.07 (m, 1 H) 6.55 -6.64 (m, 1 H) 7.17-7.28 (m, 1 H) 7.89-8.00 (m, 1 H) 9.60-9.72 (m, 1 H). MS ESI/APCI Dual posi: 246[M + H]⁺. Reference Example 32-8

¹H NMR (200 MHz, CHLOROFORM-d ) δ ppm 1.21 (t, J = 7.7 Hz, 3 H) 1.37-1.68 (m, 4 H) 1.90-2.38 (m, 5 H) 2.45-2.66 (m, 2 H) 4.83-5.08 (m, 1 H) 6.56-6.70 (m, 1 H) 7.31-7.50 (m, 1 H) 7.89-8.01 (m, 1 H) 9.61-9.74 (m, 1 H). MS ESI/APCI Dual posi: 234[M + H]⁺. Reference Example 32-9

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.10-0.21 (m, 2 H) 0.48-0.57 (m, 2 H) 0.79-0.95 (m, 1 H) 1.74 (q, J = 6.6 Hz, 2 H) 4.18 (t, J = 6.6 Hz, 2 H) 7.28-7.35 (m, 1 H) 7.93- 8.00 (m, 1 H) 8.41-8.46 (m, 1 H) 9.98-10.01 (m, 1 H). MS ESI/APCI Dual posi: 192[M + H]⁺, 214[M + Na]⁺.

Reference Example 33-1 5-Methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carbaldehyde

(1) Synthesis of 5-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid

Instead of 3,4-difluorobenzaldehyde, 2-fluoro-3-methylpyridine-5-carboxylic acid (2.00 g) was used and treated by the same technique as in Reference Example 12-1 to give 5-methyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid as a colorless solid (3.57 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.23 (s, 3H) 5.09 (q, J=9.0 Hz, 2H) 8.02-8.17 (m, 1H) 8.52-8.63 (m, 1H) 13.11 (br. s, 1H).

MS ESI/APCI Dual nega: 234 [M−H]⁻.

(2) Synthesis of N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide

The compound (3.57 g) obtained in step (1) above was used and treated by the same technique as in Reference Example 16-1(1) to give N-methoxy-N,5-dimethyl-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide as a colorless oil (2.98 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.22-2.31 (m, 3H) 3.37 (s, 3H) 3.58 (s, 3H) 4.81 (q, J=8.5 Hz, 2H) 7.80-7.92 (m, 1H) 8.37-8.49 (m, 1H).

MS ESI/APCI Dual posi: 279 [M+H]⁺.

(3) Synthesis of the Titled Compound

The compound (2.66 g) obtained in step (2) above was used and treated by the same technique as in Reference Example 16-1(3) to give the titled compound as a colorless oil (2.10 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.27-2.34 (m, 3H) 4.76-4.96 (m, 2H) 7.91-8.00 (m, 1H) 8.41-8.51 (m, 1H) 9.97 (s, 1H).

MS ESI/APCI Dual posi: 220 [M+H]⁺.

In the following Reference Examples 33-2 to 33-8, a commercial grade of the corresponding halogenated aryls and a commercial grade of the corresponding alcohols were used and treated by the method described in Reference Example 33-1 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 12-1.

TABLE 12-1 Compound Salt No. Structure Analytical Data information Reference Example 33-2

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.08-0.18 (m, 2 H) 0.44-0.54 (m, 2 H) 0.77-0.91 (m, 1 H) 1.65-1.77 (m, 2 H) 2.21-2.28 (m, 3 H) 4.50 (t, J = 6.6 Hz, 2 H) 7.83-7.90 (m, 1 H) 8.39-8.49 (m, 1 H) 9.92 (s, 1 H). MS ESI/APCI Dual posi: 206[M + H]⁺. Reference Example 33-3

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.30-0.43 (m, 2 H) 0.57-0.69 (m, 2 H) 1.18-1.40 (m, 1 H) 4.25 (d, J = 7.3 Hz, 2 H) 6.80-6.92 (m, 1 H) 7.95-8.15 (m, 1 H) 8.60 (d, J = 2.3 Hz, 1 H) 9.94 (s, 1 H). MS ESI/APCI Dual posi: 178[M + H]⁺. Reference Example 33-4

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 2.37 (s, 3 H) 5.44 (s, 2 H) 6.85-6.91 (m, 1 H) 7.17-7.23 (m, 2 H) 7.33-7.39 (m, 2 H) 8.04-8.10 (m, 1 H) 8.63-8.66 (m, 1 H) 9.95- 9.97 (m, 1 H). MS EI posi: 227[M]⁺. Reference Example 33-5

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 5.45 (s, 2 H) 6.87- 6.92 (m, 1 H) 7.33-7.44 (m, 4 H) 8.06-8.12 (m, 1 H) 8.64 (d, J = 2.3 Hz, 1 H) 9.97 (s, 1 H). MS ESI/APCI Dual posi: 248 [M + H]⁺. MS ESI/APCI Dual nega: 246[M − H]⁻. Reference Example 33-6

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.07-0.24 (m, 2 H) 0.40-0.57 (m, 2 H) 0.75-0.93 (m, 1 H) 1.66-1.82 (m, 2 H) 4.49-4.63 (m, 2 H) 8.11 (d, J = 2.2 Hz, 1 H) 8.51 (d, J = 2.2 Hz, 1 H) 9.93 (s, 1 H). MS ESI/APCI Dual posi: 226[M + H]⁺. Reference Example 33-7

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.35-0.47 (m, 2 H) 0.61-0.73 (m, 2 H) 1.31-1.47 (m, 1 H) 4.49 (d, J = 7.4 Hz, 2 H) 7.10 (dd, J = 9.1, 0.9 Hz, 1 H) 7.95 (d, J = 9.1 Hz, 1 H) 10.24 (d, J = 0.9 Hz, 1 H). MS ESI/APCI Dual posi: 179[M + H]⁺. Reference Example 33-8

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.32-0.45 (m, 2 H) 0.58-0.73 (m, 2 H) 1.22-1.41 (m, 1 H) 4.28 (d, J = 7.1 Hz, 2 H) 8.32 (d, J = 1.4 Hz, 1 H) 8.72 (d, J = 1.4 Hz, 1 H) 10.05 (s, 1 H). MS ESI/APCI Dual posi: 179[M + H]⁺.

Reference Example 34-1 3-Phenylcyclopentanecarbaldehyde

(1) Synthesis of (3-phenylcyclopentyl)methanol

Instead of ethyl cis-2-phenylcyclopropanecarboxylate, 3-phenyl-cyclopentanecarboxylic acid methyl ester (1.76 g) was used and treated by the same technique as in Reference Example 23-1(2) to give (3-phenylcyclopentyl)methanol as a colorless oil (1.31 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26-1.48 (m, 2H) 1.54-2.19 (m, 5H) 2.29-2.49 (m, 1H) 2.97-3.16 (m, 1H) 3.53-3.67 (m, 2H) 7.12-7.35 (m, 5H).

MS EI posi: 176 [M]⁺.

(2) Synthesis of the Titled Compound

The compound (0.90 g) obtained in step (1) above was used and treated by the same technique as in Reference Example 19-1 to give the titled compound as a yellow oil (0.90 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.56-2.55 (m, 7H) 2.90-3.19 (m, 1H) 7.14-7.40 (m, 5H) 9.65-9.78 (m, 1H).

In the following Reference Examples 34-2 and 34-3, a commercial grade of the corresponding esters was used and treated by the method described in Reference Example 34-1 or a modification thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 13-1.

TABLE 13-1 Compound Salt No. Structure Analytical Data information Reference Example 34-2

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.37-1.76 (m, 4 H) 2.00-2.38 (m, 5 H) 4.03-4.19 (m, 1 H) 6.78-7.02 (m, 4 H) 9.64-9.73 (m, 1 H). Reference Example 34-3

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.41-1.85 (m, 4 H) 2.01-2.45 (m, 5 H) 4.19-4.38 (m, 1 H) 6.90-6.99 (m, 2 H) 7.46-7.58 (m, 2 H) 9.69 (s, 1 H).

Reference Example 35-1 4-{[(6-Methylpyridin-3-yl)oxy]methyl}benzaldehyde

Instead of 4-hydroxybenzaldehyde and (bromomethyl)cyclobutane, 5-hydroxy-2-methylpyridine (767 mg) and 4-(chloromethyl)benzyl alcohol (1.00 g) were respectively used and treated by the same techniques as in Reference Examples 9-1 and 19-1 to give the titled compound as a pale yellow solid (1.65 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.50 (s, 3H) 5.17 (s, 2H) 7.05-7.11 (m, 1H) 7.14-7.20 (m, 1H) 7.57-7.63 (m, 2H) 7.89-7.94 (m, 2H) 8.25-8.29 (m, 1H) 10.03 (s, 1H).

MS ESI/APCI Dual posi: 228 [M+H]⁺.

MS ESI/APCI Dual nega: 226 [M−H]⁻, 262 [M+Cl]⁻.

Reference Example 36-1 cis-4-[(4-Chlorobenzyl)oxy]cyclohexanecarbaldehyde

(1) Synthesis of ethyl cis-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate and ethyl trans-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate

Instead of 4-hydroxybenzaldehyde and (bromomethyl)cyclobutane, ethyl 4-hydroxycyclohexanecarboxylate (2.00 g) and 4-chlorobenzylbromide (2.86 g) were respectively used and treated by the same technique as in Reference Example 9-1 to give ethyl cis-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate as a colorless oil (0.33 g) and ethyl trans-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate as a pale yellow oil (0.47 g).

Ethyl cis-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.1 Hz, 3H) 1.52-1.78 (m, 4H) 1.83-2.06 (m, 4H) 2.30-2.50 (m, 1H) 3.54-3.66 (m, 1H) 4.17 (q, J=7.1 Hz, 2H) 4.51 (s, 2H) 7.25-7.40 (m, 4H).

Ethyl trans-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17-1.57 (m, 7H) 1.95-2.18 (m, 4H) 2.20-2.35 (m, 1H) 3.25-3.41 (m, 1H) 4.11 (q, J=7.1 Hz, 2H) 4.51 (s, 2H) 7.21-7.37 (m, 4H).

(2) Synthesis of {cis-4-[(4-chlorobenzyl)oxy]cyclohexyl}methanol

The compound cis-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate (0.33 g) obtained in step (1) above was used and treated by the same technique as in Reference Example 23-1(2) to give {cis-4-[(4-chlorobenzyl)oxy]cyclohexyl}methanol as a colorless oil (0.29 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.67 (m, 8H) 1.83-2.02 (m, 2H) 3.49 (d, J=5.9 Hz, 2H) 3.59-3.67 (m, 1H) 4.46 (s, 2H) 7.24-7.35 (m, 4H).

(3) Synthesis of the Titled Compound

The compound (283 mg) obtained in step (2) above was used and treated by the same technique as in Reference Example 19-1 to give the titled compound as a yellow oil (257 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49-1.99 (m, 8H) 2.20-2.35 (m, 1H) 3.51-3.65 (m, 1H) 4.47 (s, 2H) 7.22-7.35 (m, 4H) 9.59-9.68 (m, 1H).

MS ESI/APCI Dual posi: 275 [M+Na]⁺.

Reference Example 36-2 trans-4-[(4-Chlorobenzyl)oxy]cyclohexanecarbaldehyde

The ethyl trans-4-[(4-chlorobenzyl)oxy]cyclohexanecarboxylate (856 mg) obtained in Reference Example 36-1(1) was used and treated by the same techniques as in Reference Example 36-1(2) and (3) to give the titled compound as a yellow oil (388 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23-1.50 (m, 4H) 1.98-2.31 (m, 5H) 3.26-3.41 (m, 1H) 4.52 (s, 2H) 7.22-7.36 (m, 4H) 9.62-9.67 (m, 1H).

Reference Example 36-3 trans-4-[(5-Chloro-2-pyridinyl)methoxy]cyclohexanecarbaldehyde

Instead of 4-chlorobenzylbromide, 2-(bromomethyl)-5-chloropyridine (5.23 g) was used and treated by the same technique as in Reference Example 36-1 to give the titled compound as a colorless oil (0.25 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28-1.67 (m, 4H) 1.99-2.31 (m, 5H) 3.33-3.52 (m, 1H) 4.65 (s, 2H) 7.39-7.48 (m, 1H) 7.64-7.75 (m, 1H) 8.48-8.54 (m, 1H) 9.61-9.71 (m, 1H).

Reference Example 37-1 trans-4-Phenoxycyclohexanecarbaldehyde

(1) Synthesis of methyl trans-4-phenoxycyclohexanecarboxylate

Instead of 4-hydroxybenzaldehyde and 2-cyclopropylethanol, phenol (1.43 g) and methyl cis-4-hydroxycyclohexanecarboxylate (2.00 g) were respectively used and treated by the same technique as in Reference Example 11-1 to give methyl trans-4-phenoxycyclohexanecarboxylate as a colorless oil (1.33 g).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.43-1.65 (m, 4H) 2.03-2.13 (m, 2H) 2.15-2.23 (m, 2H) 2.32-2.44 (m, 1H) 3.68 (s, 3H) 4.15-4.26 (m, 1H) 6.86-6.97 (m, 3H) 7.23-7.31 (m, 2H).

MS ESI/APCI Dual posi: 235 [M+H]⁺.

(2) Synthesis of (trans-4-phenoxycyclohexyl)methanol

The compound (1.31 g) obtained in step (1) above was used and treated by the same technique as in Reference Example 23-1(2) to give (trans-4-phenoxycyclohexyl)methanol as a colorless oil (897 mg).

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.96-1.70 (m, 6H) 1.81-2.01 (m, 2H) 2.10-2.31 (m, 2H) 3.50 (d, J=6.2 Hz, 2H) 4.04-4.27 (m, 1H) 6.82-7.00 (m, 3H) 7.16-7.35 (m, 2H).

MS ESI/APCI Dual posi: 207 [M+H]⁺.

(3) Synthesis of the Titled Compound

The compound (897 mg) obtained in step (2) above was used and treated by the same technique as in Reference Example 19-1 to give the titled compound as a yellow oil (801 mg).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.42-1.64 (m, 4H) 2.04-2.22 (m, 4H) 2.27-2.37 (m, 1H) 4.16-4.28 (m, 1H) 6.86-6.98 (m, 3H) 7.23-7.33 (m, 2H) 9.69 (s, 1H).

In the following Reference Examples 37-2 to 37-8, a commercial grade of the corresponding phenols and a commercial grade of the corresponding alcohols were used and treated by the method described in Reference Example 37-1 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 14-1.

TABLE 14-1 Compound Salt No. Structure Analytical Data information Reference Example 37-2

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.39-1.83 (m, 4 H) 1.97-2.38 (m, 5 H) 4.83-5.02 (m, 1 H) 6.58-6.71 (m, 1 H) 7.23-7.40 (m, 1 H) 7.89-8.05 (m, 1 H) 9.64-9.72 (m, 1 H). Reference Example 37-3

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.42-1.65 (m, 4 H) 1.99-2.36 (m, 8 H) 4.88-5.04 (m, 1 H) 6.56-6.64 (m, 1 H) 7.33-7.43 (m, 1 H) 7.88-7.99 (m, 1 H) 9.61-9.72 (m, 1 H). Reference Example 37-4

¹H NMR (600 MHz, CHLOROFORM-d ) δ ppm 1.41-2.13 (m, 8 H) 2.26-2.37 (m, 1 H) 4.41-4.53 (m, 1 H) 6.84-6.96 (m, 3 H) 7.23-7.30 (m, 2 H) 9.63-9.70 (m, 1 H). Reference Example 37-5

MS ESI/APCI Dual posi: 224[M + H]⁺. Reference Example 37-6

MS ESI/APCI Dual posi: 223[M + H]⁺. Reference Example 37-7

MS ESI/APCI Dual posi: 274[M + H]⁺. Reference Example 37-8

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.43-0.51 (m, 2 H) 0.52-0.62 (m, 2 H) 1.24 (s, 3 H) 3.81 (s, 2 H) 6.95-7.03 (m, 2 H) 7.79-7.86 (m, 2 H) 9.88 (s, 1 H). MS ESI/APCI Dual posi: 191[M + H]⁺.

Reference Example 38-1 4-({[6-(Trifluoromethyl)pyridin-3-yl]oxy}methyl)benzaldehyde

(1) Synthesis of 4-({[6-(trifluoromethyl)pyridin-3-yl]oxy}methyl)benzonitrile

Instead of 4-hydroxybenzaldehyde and bromocyclopropane, 6-(trifluoromethyl)pyridin-3-ol (1.21 g) and 4-cyanobenzylbromide (1.45 g) were respectively used and treated by the same technique as in Reference Example 10-1 to give 4-({[6-(trifluoromethyl)pyridin-3-yl]oxy}methyl)benzonitrile as a pale brown solid (1.99 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 5.23 (s, 2H) 7.34 (dd, J=8.7, 2.8 Hz, 1H) 7.52-7.59 (m, 2H) 7.64 (d, J=8.7 Hz, 1H) 7.69-7.77 (m, 2H) 8.46 (d, J=2.8 Hz, 1H).

MS ESI/APCI Dual posi: 279 [M+H]⁺.

MS ESI/APCI Dual nega: 277 [M−H]⁻.

(2) Synthesis of the Titled Compound

The compound (1.99 g) obtained in step (1) above was used and treated by the same technique as in Reference Example 16-1(3) to give the titled compound as a pale yellow solid (980 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 5.26 (s, 2H) 7.35 (dd, J=8.8, 3.0 Hz, 1H) 7.58-7.67 (m, 3H) 7.91-7.98 (m, 2H) 8.48 (d, J=3.0 Hz, 1H) 10.05 (s, 1H).

MS ESI/APCI Dual posi: 282 [M+H]⁺.

Reference Example 38-2 4-({[5-(Trifluoromethyl)pyridin-2-yl]oxy}methyl)benzaldehyde

Instead of 6-(trifluoromethyl)pyridin-3-ol and 4-cyanobenzylbromide, 4-(hydroxymethyl)benzonitrile (1.87 g) and 2-fluoro-5-(trifluoromethyl)pyridine (1.55 g) were respectively used and treated by the same technique as in Reference Example 38-1 to give the titled compound as a pale yellow solid (1.49 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 5.53 (s, 2H) 6.90-6.97 (m, 1H) 7.58-7.65 (m, 2H) 7.82 (dd, J=8.9, 2.3 Hz, 1H) 7.87-7.94 (m, 2H) 8.40-8.47 (m, 1H) 10.03 (s, 1H).

MS ESI/APCI Dual posi: 282 [M+H]⁺.

Reference Example 39-1 trans-4-[(4-Fluorobenzyl)oxy]cyclohexanecarbaldehyde

(1) Synthesis of trans-4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide

Instead of 4-(bromomethyl)benzoic acid, trans-4-hydroxycyclohexanecarboxylic acid (7.21 g) was used and treated by the same technique as in Reference Example 16-1(1) to give trans-4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide as a colorless oil (8.52 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21-1.40 (m, 2H) 1.49-1.68 (m, 2H) 1.78-1.90 (m, 2H) 2.00-2.13 (m, 2H) 2.54-2.73 (m, 2H) 3.18 (s, 3H) 3.57-3.74 (m, 4H).

(2) Synthesis of trans-4-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylcyclohexanecarboxamide

To a solution in N,N-dimethylformamide (91 mL) of the compound (8.52 g) obtained in step (1) above, imidazole (4.03 g) and tert-butyldimethylchlorosilane (6.86 g) were added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and water was added to the resulting residue. After extraction with ethyl acetate, the combined organic layers were washed with water and saturated brine. The washed organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-75:25) to give the titled compound as a colorless oil (10.5 g).

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.06 (s, 6H) 0.88 (s, 9H) 1.15-1.69 (m, 4H) 1.71-2.08 (m, 4H) 2.50-2.73 (m, 1H) 3.17 (s, 3H) 3.48-3.75 (m, 4H).

(3) Synthesis of trans-4-[(4-fluorobenzyl)oxy]-N-methoxy-N-methylcyclohexanecarboxamide

To a solution in acetonitrile (11 mL) of the compound (1.00 g) obtained in step (2) above, triethylsilane (579 mg) was added. Bismuth tribromide (104 mg) and 4-fluorobenzaldehyde (617 mg) were added under cooling with ice and the mixture was stirred at room temperature for two hours. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added and the insoluble matter was removed by filtration through Celite (registered trademark). The organic layer in the filtrate was separated and washed with saturated brine. The washed organic layer was dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) to give the titled compound as a colorless oil (0.61 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23-1.43 (m, 2H) 1.47-1.65 (m, 2H) 1.79-1.93 (m, 2H) 2.10-2.23 (m, 2H) 2.57-2.74 (m, 1H) 3.18 (s, 3H) 3.29-3.43 (m, 1H) 3.70 (s, 3H) 4.52 (s, 2H) 6.97-7.08 (m, 2H) 7.25-7.36 (m, 2H).

(4) Synthesis of the Titled Compound

The compound (0.59 g) obtained in step (3) above was used and treated by the same technique as in Reference Example 23-1(2) to give the titled compound as a yellow oil (0.46 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27-1.49 (m, 4H) 1.97-2.34 (m, 5H) 3.25-3.41 (m, 1H) 4.52 (s, 2H) 6.97-7.08 (m, 2H) 7.25-7.36 (m, 2H) 9.62-9.70 (m, 1H).

In the following Reference Examples 39-2 to 39-7, a commercial grade of the corresponding aldehydes was used and treated by the method described in Reference Example 39-1 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 15-1.

TABLE 15-1 Compound Salt No. Structure Analytical Data information Reference Example 39-2

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.22-1.49 (m, 4 H) 1.99-2.18 (m, 4 H) 2.18-2.31 (m, 1 H) 3.28-3.41 (m, 1 H) 4.56 (s, 2 H) 7.23-7.39 (m, 5 H) 9.61-9.69 (m, 1 H). Reference Example 39-3

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 0.14-0.24 (m, 2 H) 0.48-0.59 (m, 2 H) 0.96-1.13 (m, 1 H) 1.17-1.43 (m, 4 H) 1.93-2.30 (m, 5 H) 3.14-3.33 (m, 3 H) 9.62-9.67 (m, 1H). Reference Example 39-4

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.20-1.42 (m, 4 H) 1.92-2.29 (m, 5 H) 2.87 (t, J = 7.3 Hz, 2 H) 3.14-3.29 (m, 1 H) 3.67 (t, J = 7.3 Hz, 2 H) 7.15-7.36 (m, 5 H) 9.61- 9.67 (m, 1 H). Reference Example 39-5

¹H NMR (300 MHz, CHLOROFORM-d ) δ ppm 1.13-1.40 (m, 6 H) 1.44-1.81 (m, 7 H) 1.85-2.30 (m, 5 H) 3.08-3.25 (m, 1 H) 3.32 (d, J = 7.1 Hz, 2 H) 9.62-9.69 (m, 1 H). Reference Example 39-6

¹H NMR (200 MHz, CHLOROFORM-d ) δ ppm 1.21-1.51 (m, 4 H) 1.93-2.31 (m, 5 H) 2.34 (s, 3 H) 3.20-3.43 (m, 1 H) 4.52 (s, 2 H) 7.09-7.28 (m, 4 H) 9.61-9.68 (m, 1 H). Reference Example 39-7

¹H NMR (200 MHz, CHLOROFORM-d ) δ ppm 1.17-1.77 (m, 6 H) 1.80-2.29 (m, 9 H) 3.11-3.33 (m, 1 H) 3.90-4.13 (m, 1 H) 9.59-9.68 (m, 1 H).

Reference Example 40-1 4-(Piperidin-1-ylcarbonyl)benzaldehyde

To a solution of 4-carboxybenzaldehyde (1.06 g) in chloroform (14.1 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.03 g), 1-hydroxybenzotriazole monohydrate (1.62 g) and piperdine (1.05 mL) were added. After stirring the mixture at room temperature for 15 hours, a saturated aqueous solution of ammonium chloride was added. After extraction with ethyl acetate, the combined organic layers were washed with saturated brine. The washed organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=85:15-30:70) to give the titled compound as a colorless oil (1.57 g). ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.50-1.53 (m, 2H) 1.65-1.73 (m, 4H) 3.24-3.35 (m, 2H) 3.68-3.79 (m, 2H) 7.52-7.57 (m, 2H) 7.90-7.96 (m, 2H) 10.05 (s, 1H).

MS ESI/APCI Dual posi: 218 [M+H]⁺.

MS ESI/APCI Dual nega: 232 [M+Cl]⁻.

In the following Reference Examples 40-2 to 40-8, a commercial grade of the corresponding amines was used and treated by the method described in Reference Example 40-1 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 16-1.

TABLE 16-1 Compound Salt No. Structure Analytical Data information Reference Example 40-2

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.00 (t, J = 7.4 Hz, 3 H) 1.66 (sxt, J = 7.4 Hz, 2 H) 3.42-3.47 (m, 2 H) 6.16 (br. s., 1 H) 7.88-7.92 (m, 2 H) 7.92-7.96 (m, 2 H) 10.07 (s, 1 H). MS ESI/APCI Dual posi: 192[M + H]⁺. MS ESI/APCI Dual nega: 190[M − H]⁻, 226[M + Cl]⁻. Reference Example 40-3

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.63 (br. s., 6 H) 3.03 (q, J = 7.2 Hz, 2 H) 3.61 (br. s., 2 H) 7.97 (d, J = 8.1 Hz, 2 H) 8.14 (d, J = 8.1 Hz, 2 H) 9.44-9.67 (m, 1 H) 10.08 (s, 1 H). MS ESI/APCI Dual posi: 221[M + H]⁺. MS ESI/APCI Dual nega: 219[M − H]⁻. Reference Example 40-4

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.11 (s, 3 H) 3.71-3.81 (m, 2 H) 4.29-4.37 (m, 2 H) 6.71 (br. s., 1 H) 7.88-8.00 (m, 4 H) 10.09 (s, 1 H). MS ESI/APCI Dual posi: 258[M + Na]⁺. MS ESI/APCI Dual nega: 234[M − H]⁻. Reference Example 40-5

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.01-2.20 (m, 2 H) 2.42 (t, J = 8.4 Hz, 2 H) 3.38-3.73 (m, 6 H) 7.57-7.77 (m, 1 H) 7.87-8.03 (m, 4 H) 10.07 (s, 1 H). MS ESI/APCI Dual posi: 283[M + Na]⁺. MS ESI/APCI Dual nega: 259[M − H]⁻. Reference Example 40-6

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.78 (d, J = 4.5 Hz, 2 H) 7.19-7.28 (m, 1 H) 7.29-7.39 (m, 1 H) 7.66-7.76 (m, 1 H) 7.77-7.85 (m, 1 H) 7.89-8.11 (m, 4 H) 8.52-8.64 (m, 1 H) 10.09 (s, 1 H). MS ESI/APCI Dual posi: 241[M+ H]⁺, 263[M + Na]⁺. MS ESI/APCI Dual nega: 239[M − H]⁻. Reference Example 40-7

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.07-3.17 (m, 2 H) 3.88 (dd, J = 6.5, 5.7 Hz, 2 H) 7.16-7.26 (m, 2 H) 7.58-7.73 (m, 1 H) 7.82-8.01 (m, 5 H) 8.47-8.67 (m, 1 H) 10.08 (s, 1 H). MS ESI/APCI Dual posi: 255[M + H]⁺, 277[M + Na]⁺. MS ESI/APCI Dual nesa: 253[M − H]⁻. Reference Example 40-8

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9 H) 4.16 (d, J = 5.0 Hz, 2 H) 6.75 (br. s., 1 H) 7.96 (s, 4 H) 10.09 (s, 1 H). MS ESI/APCI Dual posi: -286[M + Na]⁺. MS ESI/APCI Dual nega: 262[M − H]⁻.

Reference Example 41-1 5-(4-Methylphenoxyl)pyrazine-2-carbaldehyde

(1) Synthesis of methyl 5-(4-methylphenoxyl)pyrazine-2-carboxylate

Instead of 4-hydroxybenzotrifluoride and 6-bromo-3-pyridinecarboxyaldehyde, p-cresol (833 mg) and methyl 5-chloro-2-pyrazinecarboxylate (1.33 g) were respectively used and treated by the same technique as in Reference Example 13-1 to give methyl 5-(4-methylphenoxyl)pyrazine-2-carboxylate as a colorless solid (1.36 g). ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.39 (s, 3H) 4.01 (s, 3H) 7.03-7.09 (m, 2H) 7.18-7.33 (m, 2H) 8.48 (d, J=1.2 Hz, 1H) 8.83 (d, J=1.2 Hz, 1H).

MS ESI/APCI Dual posi: 245 [M+H]⁺.

(2) Synthesis of the Titled Compound

The compound (1.36 g) obtained in step (1) above was used and treated by the same technique as in Reference Example 16-1(3) to give the titled compound as a colorless solid (1.10 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.40 (s, 3H) 7.02-7.10 (m, 2H) 7.22-7.31 (m, 2H) 8.51 (d, J=1.2 Hz, 1H) 8.71 (d, J=1.2 Hz, 1H) 10.08 (s, 1H).

MS ESI/APCI Dual posi: 215 [M+H]⁺.

Reference Example 41-2 5-(4-Chlorophenoxyl)pyrazine-2-carbaldehyde

Instead of p-cresol, 4-chlorophenol (2.23 g) was used and treated by the same technique as in Reference Example 41-1 to give the titled compound as a pale yellow solid (0.45 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.08-7.20 (m, 2H) 7.36-7.49 (m, 2H) 8.55 (d, J=1.4 Hz, 1H) 8.67-8.72 (m, 1H) 10.09 (s, 1H).

MS ESI/APCI Dual posi: 235 [M+H]⁺.

Reference Example 41-3 5-(4-Cyclopropylphenoxyl)pyrazine-2-carbaldehyde

(1) Synthesis of 5-(4-bromophenoxy)pyrazine-2-carbaldehyde

Instead of p-cresol, 4-bromophenol (5.01 g) was used and treated by the same technique as in Reference Example 41-1 to give 5-(4-bromophenoxy)pyrazine-2-carbaldehyde as a pale brown solid (1.88 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.09 (d, J=9.0 Hz, 2H) 7.58 (d, J=9.0 Hz, 2H) 8.55 (d, 3=1.2 Hz, 1H) 8.70 (s, 1H) 10.09 (s, 1H).

MS ESI/APCI Dual posi: 279 [M+H]⁺.

(2) Synthesis of 2-(4-bromophenoxy)-5-(1,3-dioxolan-2-yl)pyrazine

To a solution in toluene (20 mL) of the compound (1.66 g) obtained in step (1) above, ethylene glycol (1.11 g) and p-toluenesulfonic acid monohydrate (56.6 mg) were added and, thereafter, the mixture was stirred at 140° C. for an hour using a Dean-Stark apparatus. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to it under cooling with ice and extraction was conducted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (n-hexane:ethyl acetate=100:0-60:40) gave 2-(4-bromophenoxy)-5-(1,3-dioxolan-2-yl)pyrazine as a colorless solid (1.78 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.01-4.24 (m, 4H) 5.92 (s, 1H) 7.05 (d, J=9.0 Hz, 2H) 7.48-7.59 (m, 2H) 8.26-8.30 (m, 1H) 8.40-8.44 (m, 1H).

MS ESI/APCI Dual posi: 323 [M+H]⁺.

(3) Synthesis of 2-(4-cyclopropylphenoxy)-5-(1,3-dioxolan-2-yl)pyrazine

The compound (1.73 g) obtained in step (2) above was used and treated by the same technique as in Reference Example 14-5(2) to give 2-(4-cyclopropylphenoxy)-5-(1,3-dioxolan-2-yl)pyrazine as a brown oil (2.46 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.65-0.74 (m, 2H) 0.91-1.02 (m, 2H) 1.84-1.98 (m, 1H) 4.02-4.23 (m, 4H) 5.91 (s, 1H) 6.98-7.07 (m, 2H) 7.09-7.16 (m, 2H) 8.26-8.30 (m, 1H) 8.35-8.42 (m, 1H).

MS ESI/APCI Dual posi: 285 [M+H]⁺.

(4) Synthesis of the Titled Compound

To a solution in acetone (107 mL) of the compound (2.46 g) obtained in step (3) above, p-toluenesulfonic acid monohydrate (2.04 g) was added and the mixture was stirred at 50° C. for two hours. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to it under cooling with ice and two extractions were conducted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate; thereafter, the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-80:20) to give the titled compound as a colorless solid (0.67 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.66-0.78 (m, 2H) 0.91-1.05 (m, 2H) 1.87-2.00 (m, 1H) 7.01-7.10 (m, 2H) 7.12-7.20 (m, 2H) 8.51 (s, 1H) 8.71 (s, 1H) 10.08 (s, 1H).

MS ESI/APCI Dual posi: 241 [M+H]⁺.

Reference Example 41-4 2-(4-Methylphenoxyl)pyrimidine-5-carbaldehyde

(1) Synthesis of 2-chloro-5-(1,3-dioxolan-2-yl)pyrimidine

The compound 2-chloropyrimidine-5-carbaldehyde (1.00 g) was used and treated by the same technique as in Reference Example 41-3(2) to give 2-chloro-5-(1,3-dioxolan-2-yl)pyrimidine as a pale yellow oil (290 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.96-4.21 (m, 4H) 5.89 (s, 1H) 8.71 (s, 2H).

MS ESI/APCI Dual posi: 187 [M+H]⁺.

(2) Synthesis of 5-(1,3-dioxolan-2-yl)-2-(4-methylphenoxyl)pyrimidine

The compound (290 mg) obtained in step (1) above was used and treated by the same technique as in Reference Example 13-1 to give 5-(1,3-dioxolan-2-yl)-2-(4-methylphenoxyl)pyrimidine as a colorless solid (380 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.37 (s, 3H) 3.97-4.19 (m, 4H) 5.83 (s, 1H) 7.04-7.10 (m, 2H) 7.19-7.26 (m, 2H) 8.61 (s 2H).

MS ESI/APCI Dual posi: 259 [M+H]⁺.

(3) Synthesis of the Titled Compound

The compound (380 mg) obtained in step (2) above was used and treated by the same technique as in Reference Example 41-3(4) to give the titled compound as a colorless solid (139 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.39 (s, 3H) 7.09 (d, J=8.3 Hz, 2H) 7.26 (d, J=8.3 Hz, 2H) 9.01 (s, 2H) 9.99-10.09 (m, 1H).

MS ESI/APCI Dual posi: 215 [M+H]⁺.

Reference Example 42-1 1-(Pyrimidin-2-yl)piperidine-4-carbaldehyde

(1) Synthesis of [1-(pyrimidin-2-yl)piperidin-4-yl]methanol

To a solution of 4-piperidinemethanol (1.00 g) in dimethyl sulfoxide (28.9 mL), 2-chloropyrimidine (994 mg) and potassium carbonate (2.40 g) were added and the mixture was stirred at 100° C. for three hours. After cooling the reaction mixture to room temperature, water was added to it and extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give [1-([pyrimidin-2-yl)piperidin-4-yl]methanol as a colorless oil (1.50 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14-1.32 (m, 2H) 1.72-1.89 (m, 3H) 2.82-2.96 (m, 2H) 3.53 (d, J=5.9 Hz, 2H) 4.74-4.85 (m, 2H) 6.41-6.47 (m, 1H) 8.26-8.33 (m, 2H).

MS ESI/APCI Dual posi: 194 [M+H]⁺.

(2) Synthesis of the Titled Compound

The compound (1.50 g) obtained in step (1) above was used and treated by the same technique as in Reference Example 19-1 to give the titled compound as a yellow oil (1.21 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.57-1.72 (m, 2H) 1.94-2.05 (m, 2H) 2.49-2.61 (m, 1H) 3.12-3.24 (m, 2H) 4.53-4.64 (m, 2H) 6.48 (t, J=4.7 Hz, 1H) 8.31 (d, J=4.7 Hz, 2H) 9.70 (d, J=0.9 Hz, 1H).

MS ESI/APCI Dual posi: 192 [M+H]⁺.

Reference Example 42-2 1-(Cyclopropylacetyl)piperidine-4-carbaldehyde

(1) Synthesis of 2-cyclopropyl-1-[4-(hydroxymethyl)piperidin-1-yl]ethanone

Instead of 4-(bromomethyl)benzoic acid and N,O-dimethylhydroxylamine hydrochloride, cyclopropylacetic acid (869 mg) and 4-piperidinemethanol (1.00 g) were respectively used and treated by the same technique as in Reference Example 16-1(1) to give the titled compound as a colorless oil (1.25 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.12-0.23 (m, 2H) 0.51-0.60 (m, 2H) 0.96-1.30 (m, 3H) 1.54-1.90 (m, 3H) 2.28 (d, J=6.7 Hz, 2H) 2.47-2.65 (m, 1H) 2.95-3.10 (m, 1H) 3.43-3.59 (m, 2H) 3.80-3.94 (m, 1H) 4.60-4.76 (m, 1H).

MS ESI/APCI Dual posi: 198 [M+H]⁺.

(2) Synthesis of the Titled Compound

The compound (1.25 g) obtained in step (1) above was used and treated by the same technique as in Reference Example 19-1 to give the titled compound as a yellow oil (800 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.13-0.22 (m, 2H) 0.52-0.61 (m, 2H) 0.96-1.10 (m, 1H) 1.50-1.71 (m, 2H) 1.88-2.03 (m, 2H) 2.29 (d, J=6.8 Hz, 2H) 2.45-2.59 (m, 1H) 2.92-3.04 (m, 1H) 3.11-3.25 (m, 1H) 3.72-3.84 (m, 1H) 4.29-4.41 (m, 1H) 9.68 (s, 1H).

MS ESI/APCI Dual posi: 196 [M+H]⁺.

Reference Example 43-1 1-(Pyrimidin-2-yl)azetidine-3-carbaldehyde

(1) Synthesis of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate

To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (5.00 g) in tetrahydrofuran (62.1 mL), 1,1′-carbonyldiimidazole (6.05 g) was added and the mixture was stirred at room temperature for an hour. To the reaction mixture, a solution of N,O-dimethylhydroxylamine hydrochloride (3.64 g) and triethylamine (4.02 g) in acetonitrile (62.1 mL) was added and the mixture was stirred at the same temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and water was added to the resulting residue. Extraction was conducted with ethyl acetate and the combined organic layers were washed with an aqueous solution of 5% citric acid and saturated brine. The washed organic layers were dried over anhydrous sodium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate as a pale yellow oil (7.30 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9H) 3.21 (s, 3H) 3.56-3.68 (m, 4H) 4.00-4.09 (m, 2H) 4.09-4.19 (m, 2H).

(2) Synthesis of N-methoxy-N-methyl-1-(pyrimidin-2-yl)azetidine-3-carboxamide

To a solution in chloroform (24.8 mL) of the compound (7.30 g) obtained in step (1) above, trifluoroacetic acid (12.4 mL) was added and the mixture was stirred at room temperature for 15 hours and then concentrated under reduced pressure. The resulting residue (6.29 g) was used and treated by the same technique as in Reference Example 42-1(1) to give N-methoxy-N-methyl-1-(pyrimidin-2-yl)azetidine-3-carboxamide as a colorless solid (810 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.23 (s, 3H) 3.70 (s, 3H) 3.80-3.96 (m, 1H) 4.16-4.41 (m, 4H) 6.51-6.59 (m, 1H) 8.28-8.35 (m, 2H).

MS ESI/APCI Dual posi: 223 [M+H]⁺.

(3) Synthesis of the Titled Compound

The compound (810 mg) obtained in step (2) above was used and treated by the same technique as in Reference Example 16-1(3) to give the titled compound as a colorless oil (707 mg).

MS ESI/APCI Dual posi: 164 [M+H]⁺.

Reference Example 44-1 tert-Butyl 4-formyl-2-methyl-1H-imidazole-1-carboxylate

To a solution of 2-methyl-1H-imidazole-4-carbaldehyde (500 mg) in chloroform (15 mL), di-tert-butyl dicarbonate (1.19 g), triethylamine (949 μL), and 4-dimethylaminopyridine were added and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with chloroform. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the titled compound as a colorless solid (883 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.64 (s, 9H) 2.68 (s, 3H) 7.98 (s, 1H) 9.85 (s, 1H).

MS ESI/APCI Dual posi: 233 [M+Na]⁺.

MS ESI/APCI Dual nega: 209 [M−H]⁻.

Reference Example 45-1 1-(4-Cyclohexyl-3-fluorophenyl)methaneamine hydrochloride

(1) Synthesis of 4-cyclohexen-1-yl-3-fluorobenzonitrile

To a mixture of 3-fluoro-4-iodobenzonitrile (1.53 g), 1-cyclohexen-1-yl-boronic acid (938 mg), bis(triphenylphosphine)palladium(II) dichloride (435 mg) and ethanol (9.75 mL), sodium ethoxide (about 20%, solution in ethanol, 5.75 mL) was added and the mixture was stirred at 90° C. for 15 minutes under irradiation with microwaves. After being cooled to room temperature, the reaction mixture was poured into water and three extractions were conducted with chloroform. The combined organic layers were washed with saturated brine and passed through a phase separator to be concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-75:25) to give the titled compound as a pale yellow oil (980 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.63-1.84 (m, 4H) 2.18-2.29 (m, 2H) 2.30-2.41 (m, 2H) 6.01-6.10 (m, 1H) 7.27-7.42 (m, 3H).

MS ESI/APCI Dual posi: 224 [M+Na]⁺.

MS ESI/APCI Dual nega: 236 [M+Cl]⁻.

(2) Synthesis of the Titled Compound

To a solution in isopropyl alcohol (24 mL) of the compound (980 mg) obtained in step (1) above, a solution (3.7 mL) of 4 mol/L hydrogen chloride in 1,4-dioxane and 20% palladium hydroxide/carbon (98 mg) were added. The mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in ethanol (10 mL), a solution (2.0 mL) of 2 mol/L hydrogen chloride in methanol and 20% palladium hydroxide/carbon (98 mg) were added. The mixture was stirred at room temperature for 26 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. To the resulting residue, ethanol (5 mL) and diethyl ether (50 mL) were added and the mixture was stirred for 15 minutes. The resulting precipitate was recovered by filtration to give the titled compound as a brown solid (1.06 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.14-1.54 (m, 5H) 1.63-1.86 (m, 5H) 2.70-2.87 (m, 1H) 3.99 (s, 2H) 7.22-7.42 (m, 3H) 8.43 (br. s., 2H).

MS ESI/APCI Dual posi: 208 [M+H]⁺.

Reference Example 45-2 1-[4-(Aminomethyl)phenyl]-4,4-difluorocyclohexanol hydrochloride

(1) Synthesis of 4-(4,4-difluoro-1-hydroxycyclohexyl)benzonitrile

To a solution of 4-iodobenzonitrile (5.35 g) in tetrahydrofuran (100 mL), isopropylmagnesium bromide (about 1 mol/L, solution in tetrahydrofuran, 35 mL) was added dropwise at −40° C. in an argon atmosphere. After stirring the mixture at that temperature for an hour, a solution of 4,4-difluorocyclohexanone (4.70 g) in cyclopentyl methyl ether (10 mL) was added dropwise. The mixture was brought to room temperature over a period of 5.5 hours and a saturated aqueous solution of ammonium chloride was added. Three extractions were conducted with ethyl acetate and the combined organic layers were washed with saturated brine and thereafter dried over anhydrous magnesium sulfate. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure.

The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-40:60) to give 4-(4,4-difluoro-1-hydroxycyclohexyl)benzonitrile as a colorless solid (2.19 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.77-1.92 (m, 2H) 2.00-2.45 (m, 6H) 7.58-7.72 (m, 4H).

MS EI posi: 237 [M]⁺.

(2) Synthesis of the Titled Compound

The compound (2.19 g) obtained in step (1) above was used and treated by the same technique as in Reference Example 45-1(2) to give the titled compound as a colorless solid (1.51 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.66-1.79 (m, 2H) 1.85-2.04 (m, 4H) 2.09-2.36 (m, 2H) 3.99 (s, 2H) 5.28 (s, 1H) 7.40-7.48 (m, 2H) 7.49-7.57 (m, 2H) 8.32 (br. s., 3H).

MS ESI/APCI Dual posi: 242 [M+H]⁺.

MS ESI/APCI Dual nega: 276 [M+Cl]⁻.

Reference Example 46-1 1-[trans-3-(4-Chlorophenoxyl)cyclobutyl]methaneamine

(1) Synthesis of N-benzyl-3-oxocyclobutanecarboxamide

To a solution of 3-oxocyclobutanecarboxylic acid (13.5 g) in tetrahydrofuran (135 mL), 1,1′-carbonyldiimidazole (23.0 g) was added under cooling with ice. The mixture was brought to room temperature and stirred for 90 minutes. Benzylamine (15.5 mL) was added and the mixture was stirred at that temperature for 14 hours. The crude product was adsorbed on diatomaceous earth with the solvent being distilled off under reduced pressure. The crude product adsorbed on the diatomaceous earth was purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) to give N-benzyl-3-oxocyclobutanecarboxamide as a colorless solid (16.9 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.89-3.10 (m, 1H) 3.11-3.32 (m, 2H) 3.41-3.67 (m, 2H) 4.50 (d, J=5.8 Hz, 2H) 7.25-7.42 (m, 5H).

MS ESI/APCI Dual posi: 204 [M+H]⁺.

(2) Synthesis of cis-3-[(benzylamino)methyl]cyclobutanol

The compound (16.9 g) obtained in step (1) above was used and treated by the same technique as in Reference Example 23-1(2) to give cis-3-[(benzylamino)methyl]cyclobutanol as a pale yellow oil (16.2 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.35-1.57 (m, 2H) 1.66-1.93 (m, 2H) 2.12-2.36 (m, 2H) 2.42-2.53 (m, 2H) 3.69 (s, 2H) 3.78-4.00 (m, 1H) 7.12-7.41 (m, 5H).

MS ESI/APCI Dual posi: 192 [M+H]⁺.

(3) Synthesis of cis-3-(aminomethyl)cyclobutanol

The compound (16.2 g) obtained in step (2) above was used and treated by the same technique as in Reference Example 29-1(4) to give cis-3-(aminomethyl)cyclobutanol as a colorless oil (10.4 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.29-1.51 (m, 2H) 1.53-1.70 (m, 1H) 2.08-2.29 (m, 2H) 2.41-2.51 (m, 2H) 3.76-3.98 (m, 1H).

(4) Synthesis of tert-butyl [(cis-3-hydroxycyclobutyl)methyl]carbamate

The compound (10.3 g) obtained in step (3) above was used and treated by the same technique as in Reference Example 44-1 to give tert-butyl [(cis-3-hydroxycyclobutyl)methyl]carbamate as a colorless solid (6.08 g).

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.37 (s, 9H) 1.37-1.49 (m, 2H) 1.66-1.79 (m, 1H) 2.08-2.23 (m, 2H) 2.87-2.91 (m, 2H) 3.78-3.91 (m, 1H) 4.82-4.94 (m, 1H) 6.76 (t, J=5.4 Hz, 1H).

MS ESI/APCI Dual posi: 224 [M+Na]⁺.

MS ESI/APCI Dual nega: 200 [M−H]⁻.

(5) Synthesis of tert-butyl {[trans-3-(4-chlorophenoxyl)cyclobutyl]methyl}carbamate

Instead of 4-hydroxybenzaldehyde and 2-cyclopropylethanol, 4-chlorophenol (767 mg) and the compound (1.00 g) obtained in step (4) above were respectively used and treated by the same technique as in Reference Example 11-1 to give tert-butyl {[trans-3-(4-chlorophenoxyl)cyclobutyl]methyl}carbamate as a colorless solid (1.05 g).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 2.15-2.37 (m, 4H) 2.40-2.65 (m, 1H) 3.12-3.35 (m, 2H) 4.64-4.79 (m, 1H) 6.63-6.76 (m, 2H) 7.15-7.25 (m, 2H).

(6) Synthesis of the Titled Compound

To a solution in 1,4-dioxane (30 mL) of the compound (0.98 g) obtained in step (5) above, a solution (25 mL) of 4 mol/L hydrogen chloride in 1,4-dioxane was added and the mixture was stirred at room temperature for 5 hours. After adding diethyl ether (120 mL), the mixture was stirred for another two hours and thereafter the precipitate was recovered by filtration. The recovered precipitate was dissolved in an aqueous solution of 1 mol/L sodium hydroxide and chloroform and two extractions were conducted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the titled compound as a colorless oil (660 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.12-2.48 (m, 5H) 2.74-2.87 (m, 2H) 4.61-4.77 (m, 1H) 6.63-6.80 (m, 2H) 7.12-7.27 (m, 2H).

In the following Reference Examples 46-2 to 46-4, a commercial grade of the corresponding phenols was used and treated by the method described in Reference Example 46-1 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 17-1.

TABLE 17-1 Compound Salt No. Structure Analytical Data information Reference Example 46-2

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.17-2.39 (m, 8 H) 2.82 (d, J = 7.0 Hz, 2 H) 4.58-4.82 (m, 1 H) 6.61-6.77 (m, 2 H) 6.96-7.14 (m, 2 H). MS ESI/APCI Dual posi: 192[M + H]⁺. Reference Example 46-3

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.21-2.55 (m, 5 H) 2.86 (d, J = 7.3 Hz, 2 H) 4.66-4.83 (m, 1 H) 6.74-6.91 (m, 2 H) 7.39-7.65 (m, 2 H). MS ESI/APCI Dual posi: 246[M + H]⁺, 287[M + Na]⁺. Reference Example 46-4

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.15-2.22 (m, 2 H) 2.33- 2.42 (m, 2 H) 2.47-2.57 (m, 1 H) 2.99 (d, J = 7.8 Hz, 2 H) 4.82-4.93 (m, 1 H) 6.78-6.84 (m, 1 H) 6.85-6.92 (m, 1 H) 6.97-7.02 (m, 1 H) 7.26-7.34 (m, 1 H) 7.73-8.00 (m, 3H). MS ESI/APCI Dual posi: 212[M + H]⁺.

Reference Example 46-5 1-{cis-3-[(4-Chlorobenzyl)oxy]cyclobutyl}methaneamine

(1) Synthesis of tert-butyl ({cis-3-[(4-chlorobenzyl)oxy]cyclobutyl}methyl)carbamate

Instead of 4-hydroxybenzaldehyde and (bromomethyl)cyclobutane, the compound (1.00 g) obtained in Reference Example 46-1(4) and 4-chlorobenzyl bromide (1.02 g) were respectively used and treated by the same technique as in Reference 9-1 to give tert-butyl ({cis-3-[(4-chlorobenzyl)oxy]cyclobutyl}methyl)carbamate as a colorless solid (750 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 1.58-1.71 (m, 2H) 1.88-2.10 (m, 1H) 2.25-2.43 (m, 2H) 3.08-3.22 (m, 2H) 3.81-3.95 (m, 1H) 4.36 (s, 2H) 7.20-7.37 (m, 4H).

(2) Synthesis of the Titled Compound

The compound (750 mg) obtained in step (1) above was used and treated by the same technique as in Reference Example 46-1(6) to give the titled compound as a colorless oil (523 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.52-1.71 (m, 2H) 1.77-1.95 (m, 1H) 2.27-2.45 (m, 2H) 2.72 (d, J=6.7 Hz, 2H) 3.81-4.01 (m, 1H) 4.38 (s, 2H) 7.20-7.39 (m, 4H).

MS ESI/APCI Dual posi: 226 [M+H]⁺.

Reference Example 46-6 1-[cis-3-(4-Chlorophenoxyl)cyclobutyl]methaneamine

(1) Synthesis of trans-3-[({[(2-methyl-2-propanyl)oxy]carbonyl}amino)methyl]cyclobutyl 4-nitrobenzoate

To a mixture of the compound (2.00 g) obtained in Reference Example 46-1(4), 4-nitrobenzoic acid (3.32 g), triphenylphosphine (5.21 g) and tetrahydrofuran (50 mL), diisopropyl azodicarboxylate (1.0 mol/L, solution in toluene, 10.5 mL) was added and the mixture was stirred at room temperature for 16 hours. After concentrating under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-75:25) to give trans-3-[({[(2-methyl-2-propanyl)oxy]carbonyl}amino)methyl]cyclobutyl 4-nitrobenzoate as a colorless solid (3.88 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9H) 2.24-2.45 (m, 4H) 2.46-2.68 (m, 1H) 3.21-3.33 (m, 2H) 5.29-5.41 (m, 1H) 8.18-8.25 (m, 2H) 8.26-8.32 (m, 2H).

(2) Synthesis of tert-butyl[(trans-3-hydroxycyclobutyl)methyl]carbamate

To a solution in tetrahydrofuran (100 mL) of the compound (3.88 g) obtained in step (1) above, an aqueous solution of 1 mol/L sodium hydroxide (19.9 mL) was added and the mixture was stirred at room temperature for 4 hours. Extraction was conducted with ethyl acetate and after drying the combined organic layers over anhydrous magnesium sulfate, the desiccant was removed by filtration. With the solvent being distilled off under reduced pressure, the crude product was adsorbed on diatomaceous earth. The crude product as adsorbed on the diatomaceous earth was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-0:100, then chloroform:methanol=100:0-90:10) to give tert-butyl [(trans-3-hydroxycyclobutyl)methyl]carbamate as a colorless solid (1.87 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.37 (s, 9H) 1.72-2.00 (m, 4H) 2.01-2.22 (m, 1H) 2.85-3.02 (m, 2H) 4.05-4.23 (m, 1H) 4.81-4.95 (m, 1H) 6.72-6.91 (m, 1H).

(3) Synthesis of the Titled Compound

The compound (500 mg) obtained in step (2) above was used and treated by the same techniques as in Reference 46-1(5) and (6) to give the titled compound as a colorless oil (460 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.71-1.90 (m, 2H) 1.95-2.13 (m, 1H) 2.50-2.68 (m, 2H) 2.77 (d, J=6.8 Hz, 2H) 4.43-4.60 (m, 1H) 6.66-6.80 (m, 2H) 7.14-7.26 (m, 2H).

MS ESI/APCI Dual posi: 212 [M+H]⁺.

Reference Example 46-7 1-{trans-3-[(4-Chlorobenzyl)oxy]cyclobutyl}methaneamine

The compound (1.30 mg) obtained in Reference Example 46-6(2) was used and treated by the same technique as in Reference Example 46-5 to give the titled compound as a colorless oil (630 smg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.91-2.34 (m, 5H) 2.72 (d, J=7.3 Hz, 2H) 4.03-4.20 (m, 1H) 4.36 (s, 2H) 7.20-7.38 (m, 4H).

MS ESI/APCI Dual posi: 226 [M+H]⁺.

Reference Example 47-1 2-{[tert-Butyl(dimethyl)silyl]oxy}-1-(4-iodophenyl)ethaneamine

(1) Synthesis of amino(4-iodophenyl)acetonitrile

To a solution of 4-iodobenzaldehyde (10.4 g) in methanol (36 mL), tetraisopropyl orthotitanate (50.0 mL) and a solution (50 mL) of 8 mol/L ammonia in methanol were added and the mixture was stirred at room temperature for 3.5 hours. Trimethylsilyl cyanide (5.89 mL) was slowly added to the mixture, which was then stirred at the same temperature for 14 hours. Iced water was added to the reaction mixture, which was then filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure and the resulting residue was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-25:75) to give amino(4-iodophenyl)acetonitrile as a pale yellow solid (5.05 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.87 (s, 2H) 7.27-7.33 (m, 2H) 7.69-7.83 (m, 2H).

(2) Synthesis of amino(4-iodophenyl)acetic acid hydrochloride

A suspension in 6 mol/L hydrochloric acid (65 mL) of the compound (5.05 g) obtained in Step (1) above was stirred at 105° C. for 14 hours. After being cooled to room temperature, the suspension was stirred at room temperature for an hour and then stirred for 30 minutes under cooling with ice. The resulting precipitate was recovered by filtration to give amino(4-iodophenyl)acetic acid hydrochloride as a colorless solid (4.32 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 4.18 (s, 2H) 7.08-7.30 (m, 2H) 7.60-7.77 (m, 2H).

MS ESI/APCI Dual posi: 278 [M+H]⁺.

MS ESI/APCI Dual nega: 276 [M−H]⁻.

(3) Synthesis of 2-amino-2-(4-iodophenyl)ethanol

To a liquid mixture of lithium borohydride (2.0 mol/L, solution in tetrahydrofuran, 19.7 mL) and chlorotrimethylsilane (9.97 mL), the compound (4.95 g) obtained in step (2) above was added in small portions at room temperature and the mixture was stirred for 16 hours. Under cooling with ice, methanol (3.5 mL) was added to the mixture, which was then brought to room temperature and stirred for 15 minutes. To the stirred mixture, water (19.7 mL), ethyl acetate (39.4 mL), saturated brine (19.7 mL) and sodium hydroxide (1.87 g) were added successively and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure to give 2-amino-2-(4-iodophenyl)ethanol as a yellow solid (4.70 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.43-3.59 (m, 1H) 3.65-3.77 (m, 1H) 3.94-4.10 (m, 1H) 7.02-7.15 (m, 2H) 7.62-7.75 (m, 2H).

MS ESI/APCI Dual posi: 264[1\4+H]⁺.

(4) Synthesis of the Titled Compound

To a mixture of the compound (4.70 g) obtained in step (3) above, 4-dimethylaminopyridine (48.2 mg), triethylamine (4.40 mL) and chloroform (63.2 mL), a solution of tert-butyldimethylchlorosilane (2.38 g) in chloroform (31.6 mL) was added dropwise under cooling with ice and the mixture was stirred at the same temperature for 30 minutes, and then at room temperature for three days. The reaction mixture was concentrated under reduced pressure and water and ethyl acetate were then added. Extraction was conducted with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-98:2) to give the titled compound as a pale yellow oil (4.68 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.02 (s, 6H) 0.89 (s, 9H) 3.40-3.56 (m, 1H) 3.62-3.74 (m, 1H) 3.97-4.07 (m, 1H) 7.06-7.20 (m, 2H) 7.56-7.72 (m, 2H).

Reference Example A-1 Methyl[4-({[4′-(trifluoromethyl)biphenyl-4-yl]methyl}amino)tetrahydro-2H-pyran-4-yl]acetate

To a solution in chloroform (20 mL) of the compound (500 mg) obtained in Reference Example 1-1, the compound (627 mg) obtained in Reference Example 6-2 was added and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (654 mg) was added to the mixture which was further stirred at room temperature for 12 hours. Under cooling with ice, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, which was then brought to room temperature. Three extractions were conducted with chloroform. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=80:20-0:100) to give the titled compound as a colorless oil (784 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.66-1.76 (m, 4H) 2.60 (s, 2H) 3.60-3.78 (m, 7H) 3.86-3.99 (m, 2H) 4.77 (s, 1H) 7.45-7.52 (m, 2H) 7.54-7.63 (m, 2H) 7.65-7.73 (m, 4H).

MS ESI/APCI Dual posi: 408 [M+H]⁺, 430 [M+Na]⁺.

In the following Reference Examples A-2 to A-485, the compounds obtained in Reference Examples 1-1 to 5-5, Reference Examples 28-1 to 30-2, or commercial grades of the corresponding β-alanine esters, as well as the compounds obtained in Reference Examples 6-1 to 26-1, Reference Examples 31-1 to 44-1, or commercial grades of the corresponding aldehydes or ketones were used as starting materials and treated by the method described in Reference Example A-1 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Tables 18-1 to 18-69.

TABLE 18-1 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-2

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.98 (s, 2 H) 3.89 (s, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 4.56 (d, J = 6.7 Hz, 2 H) 4.71 (d, J = 6.7 Hz, 2 H) 7.29-7.38 (m, 1 H) 7.39-7.49 (m, 4 H) 7.51-7.63 (m, 4 H). MS ESI/APCI Dual posi: 326[M + H]⁺. Reference Example A-3

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J = 6.8 Hz, 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.57-2.71 (m, 2 H) 2.80-2.92 (m, 1 H) 3.79 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.13-7.19 (m, 2 H) 7.32-7.36 (m, 2 H). MS ESI/APCI Dual posi: 306[M + H]⁺, 328[M + Na]⁺. Reference Example A-4

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.47-2.55 (m, 2 H) 2.82-2.91 (m, 2 H) 3.75 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.01-7.13 (m, 2 H) 7.56-7.70 (m, 2 H). MS ESI/APCI Dual posi: 334[M + H]⁺, 356[M + Na]⁺. Reference Example A-5

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.51 (t, J = 6.4 Hz, 2 H) 2.86 (t, J = 6.4 Hz, 2 H) 3.77 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.96-7.02 (m, 1 H) 7.10-7.17 (m, 1 H) 7.44-7.51 (m, 1 H). MS ESI/APCI Dual posi: 304[M + H]⁺, 326[M + Na]⁺. Reference Example A-6

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.51 (t, J = 6.7 Hz, 2 H) 2.85 (t, J = 6.7 Hz, 2 H) 3.73 (s, 2 H) 3.80 (s, 3 H) 3.81 (s, 3 H) 4.13 (q, J = 7.1 Hz, 2 H) 6.34- 6.51 (m, 2 H) 7.13 (d, J = 7.9 Hz, 1 H). MS ESI/APCI Dual posi: 268[M + H]⁺. Reference Example A-7

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.6 Hz, 2 H) 2.88 (t, J = 6.6 Hz, 2 H) 3.73 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.52 (ddd, J = 5.3, 1.7, 1.4 Hz, 2 H) 5.28 (ddt, J = 10.5, 1.6, 1.4 Hz, 1 H) 5.41 (dtd, J = 17.3, 1.7, 1.6 Hz, 1 H) 6.06 (ddt, J = 17.3, 10.5, 5.3 Hz, 1 H) 6.84- 6.90 (m, 2 H) 7.19-7.26 (m, 2 H). MS ESI/APCI Dual posi: 264[M + H]⁺. Reference Example A-8

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23-1.59 (m, 6 H) 1.59-1.76 (m, 4 H) 2.53 (s, 2 H) 3.67 (s, 3 H) 3.68 (s, 2 H) 7.19-7.26 (m, 1 H) 7.27-7.34 (m, 2 H) 7.35-7.41 (m, 2 H). MS ESI/APCI Dual posi: 262[M + H]⁺.

TABLE 18-2 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-9 

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29-1.59 (m, 6 H) 1.60-1.77 (m, 4 H) 2.55 (s, 2 H) 3.68 (s, 3 H) 3.72 (s, 2 H) 7.29-7.37 (m, 1 H) 7.39-7.49 (m, 4 H) 7.51-7.62 (m, 4 H). MS ESI/APCI Dual posi: 338[M + H]⁺. Reference Example A-10

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13-1.63 (m, 11 H) 1.95-2.12 (m, 2 H) 2.66 (s, 2 H) 3.76 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.09-7.43 (m, 5 H). MS ESI/APCI Dual posi: 276[M + H]⁺. Reference Example A-11

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.08-1.63 (m, 11 H) 1.93-2.15 (m, 2 H) 2.69 (s, 2 H) 3.92 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.34-7.54 (m, 3 H) 7.71 (s, 1 H) 7.74- 7.92 (m, 3 H). MS ESI/APCI Dual posi: 326[M + H]⁺. Reference Example A-12

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15-1.64 (m, 11 H) 1.99-2.14 (m, 2 H) 2.70 (s, 2 H) 3.81 (s, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 7.29-7.49 (m, 5 H) 7.48-7.65 (m, 4 H). MS ESI/APCI Dual posi: 352[M + H]⁺. Reference Example A-13

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.51-1.90 (m, 8 H) 2.64 (s, 2 H) 3.70 (s, 3 H) 3.74 (s, 2 H) 7.28-7.37 (m, 1 H) 7.38-7.47 (m, 4 H) 7.49-7.62 (m, 4 H). MS ESI/APCI Dual posi: 324[M + H]⁺. Reference Example A-14

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.66-1.76 (m, 4 H) 2.59 (s, 2 H) 3.64-3.70 (m, 5 H) 3.72 (s, 2 H) 3.90-3.96 (m, 2 H) 7.31-7.35 (m, 1 H) 7.41-7.47 (m, 4 H) 7.54- 7.60 (m, 4 H). MS ESI/APCI Dual posi: 340[M + H]⁺, 362[M + Na]⁺. Reference Example A-15

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.53-1.61 (m, 2 H) 2.07-2.13 (m, 2 H) 2.75 (s, 2 H) 3.50 (td, J = 11.5, 2.3 Hz, 2 H) 3.77-3.84 (m, 4 H) 4.21 (q, J = 7.1 Hz, 2 H) 7.31-7.37 (m, 3 H) 7.41-7.45 (m, 2 H) 7.52-7.56 (m, 2 H) 7.57-7.60 (m, 2 H). MS ESI/APCI Dual posi: 354[M + H]⁺.

TABLE 18-3 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-16

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.74-1.97 (m, 2 H) 1.97-2.19 (m, 4 H) 2.75 (s, 2 H) 3.70 (s, 3 H) 3.74 (s, 2 H) 7.29-7.37 (m, 1 H) 7.38-7.47 (m, 4 H) 7.51-7.61 (m, 4 H). MS ESI/APCI Dual posi: 310[M + H]⁺. Reference Example A-17

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J = 7.1 Hz, 3 H) 1.50-1.74 (m, 6 H) 1.97-2.14 (m, 2 H) 2.74 (s, 2 H) 3.83 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.28-7.48 (m, 5 H) 7.49- 7.63 (m, 4 H). MS ESI/APCI Dual posi: 338[M + H]⁺. Reference Example A-18

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J = 7.1 Hz, 3 H) 1.41-1.63 (m, 10 H) 1.98-2.13 (m, 2 H) 2.68 (s, 2 H) 3.81 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.28-7.48 (m, 5 H) 7.49-7.62 (m, 4 H). MS ESI/APCI Dual posi: 366[M + H]⁺. Reference Example A-19

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 1.82-2.03 (m, 4 H) 2.29-2.52 (m, 2 H) 2.94 (s, 2 H) 3.85 (s, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 7.29-7.48 (m, 5 H) 7.50- 7.63 (m, 4 H). MS ESI/APCI Dual posi: 324[M + H]⁺. Reference Example A-20

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.55 (t, J = 6.5 Hz, 2 H) 2.93 (t, J = 6.5 Hz, 2 H) 3.85 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.31-7.49 (m, 5 H) 7.51-7.63 (m, 4 H). MS ESI/APCI Dual posi: 284[M + H]⁺. Reference Example A-21

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13-1.37 (m, 9 H) 2.53 (s, 2 H) 3.76 (s, 2 H) 4.15 (q, J = 7.2 Hz, 2 H) 7.27- 7.48 (m, 5 H) 7.49-7.66 (m, 4 H). MS ESI/APCI Dual posi: 312[M + H]⁺, 334[M + Na]⁺. Reference Example A-22

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.87 (t, J = 6.4 Hz, 2 H) 3.77 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.19-7.35 (m, 4 H). MS ESI/APCI Dual posi: 242[M + H]⁺.

TABLE 18-4 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-23

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.89 (t, J = 6.4 Hz, 2 H) 3.87 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.41-7.48 (m, 2 H) 7.55 -7.60 (m, 2 H). MS ESI/APCI Dual posi: 276[M + H]⁺. Reference Example A-24

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.18 (d, J = 6.2 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.40 (dd, J = 15.1, 6.0 Hz, 1 H) 2.46- 2.58 (m, 1 H) 3.11-3.26 (m, 1 H) 3.81 (d, J = 12.9 Hz, 1 H) 3.88 (d, J = 12.9 Hz, 1 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.29- 7.39 (m, 1 H) 7.36-7.48 (m, 4 H) 7.49-7.64 (m, 4 H). MS ESI/APCI Dual posi: 298[M + H]⁺. Reference Example A-25

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.90 (t, J = 6.4 Hz, 2 H) 3.81 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.20-7.36 (m, 5 H). MS ESI/APCI Dual posi: 208[M + H]⁺. Reference Example A-26

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.18 (d, J = 7.0 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.63-2.73 (m, 2 H) 2.88-2.95 (m, 1 H) 3.79-3.88 (m, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.31- 7.35 (m, 1 H) 7.36-7.40 (m, 2 H) 7.40-7.46 (m, 2 H) 7.52- 7.57 (m, 2 H) 7.57-7.61 (m, 2 H). MS ESI/APCI Dual posi: 298[M + H]⁺. Reference Example A-27

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.51 (t, J = 6.4 Hz. 2 H) 2.87 (t, J = 6.4 Hz, 2 H) 3.75 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.15-7.24 (m, 2 H) 7.40-7.48 (m, 2 H). MS ESI/APCI Dual posi: 286[M + H]⁺. Reference Example A-28

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.93 (t, J = 6.5 Hz, 2 H) 3.87 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.28-7.64 (m, 9 H). MS ESI/APCI Dual posi: 284[M + H]⁺. Reference Example A-29

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J = 7.1 Hz, 3 H) 2.40 (t, J = 6.6 Hz, 2 H) 2.76 (t, J = 6.6 Hz, 2 H) 3.73 (s, 2 H) 4.11 (q, J = 7.1 Hz, 2 H) 7.15-7.55 (m, 9 H). MS ESI/APCI Dual posi: 284[M + H]⁺.

TABLE 18-5 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-30

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.95-1.19 (m, 2 H) 1.27 (t, J = 7.1 Hz, 3 H) 1.35-1.62 (m, 3 H) 1.82-2.00 (m. 4 H) 2.38-2.58 (m, 5 H) 2.89 (t, J = 6.5 Hz, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.12-7.23 (m, 3 H) 7.23-7.33 (m, 2 H). MS ESI/APCI Dual posi: 290[M + H]⁺. Reference Example A-31

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.09-1.35 (m, 9 H) 2.69 (s, 2 H) 3.84 (s, 2 H) 4.13 (q, J = 7.0 Hz, 2 H) 7.27- 7.49 (m, 5 H) 7.50-7.63 (m, 4 H). MS ESI/APCI Dual posi: 312[M + H]⁺. Reference Example A-32

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.91 (t, J = 6.4 Hz, 2 H) 3.78 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.94-7.02 (m, 4 H) 7.06-7.11 (m, 1 H) 7.27-7.35 (m, 4 H). MS ESI/APCI Dual posi: 300[M + H]⁺. Reference Example A-33

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.55 (t, J = 6.4 Hz, 2 H) 2.94 (t, J = 6.4 Hz, 2 H) 3.97 (s, 2 H) 4.14 (q, J = 7.1 Hz. 2 H) 7.41-7.48 (m, 3 H) 7.75 (s, 1 H) 7.78-7.84 (m, 3 H). MS ESI/APCI Dual posi: 258[M + H]⁺. Reference Example A-34

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.0 Hz, 3 H) 2.54 (t, J = 6.4 Hz, 2 H) 2.94 (t, J = 6.4 Hz, 2 H) 4.02 (s, 2 H) 4.14 (q, J = 7.0 Hz, 2 H) 7.37 (dd, J = 8.3, 4.1 Hz, 1 H) 7.56 (dd, J = 8.3, 1.7 Hz, 1 H) 7.79 (d, J = 8.3 Hz, 1 H) 7.95- 8.05 (m, 1 H) 8.13 (dd, J = 8.3, 0.8 Hz, 1 H) 8.90 (dd, J = 4.1, 1.7 Hz, 1 H). MS ESI/APCI Dual posi: 259[M + H]⁺. Reference Example A-35

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23 (t, J = 7.1 Hz, 3 H) 2.56 (t, J = 6.5 Hz, 2 H) 3.02 (t, J = 6.5 Hz, 2 H) 4.12 (q, J = 7.1 Hz, 2 H) 4.25 (s, 2 H) 7.39-7.43 (m, 1 H) 7.45- 7.50 (m, 2 H) 7.50-7.55 (m, 1 H) 7.76 (d, J = 8.3 Hz, 1 H) 7.83-7.87 (m, 1 H) 8.12 (d, J = 8.3 Hz, 1 H). MS ESI/APCI Dual posi: 258[M + H]⁺. Reference Example A-36

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.87 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.19-7.25 (m, 1 H) 7.43 (d, J = 8.1 Hz, 2 H) 7.68-7.77 (m, 2 H) 7.90-8.01 (m, 2 H) 8.69 (dt, J = 4.9, 1.4 Hz, 1 H). MS ESI/APCI Dual posi: 285[M + H]⁺.

TABLE 18-6 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-37

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.36 (s, 9 H) 2.55 (t, J = 6.5 Hz, 2 H) 2.93 (t, J = 6.5 Hz, 2 H) 3.84 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.34-7.40 (m, 2 H) 7.43-7.48 (m, 2 H) 7.50-7.57 (m, 4 H). MS ESI/APCI Dual posi: 340[M + H]⁺. Reference Example A-38

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.20-1.50 (m, 8 H) 1.69-1.94 (m, 5 H) 2.38-2.59 (m, 3 H) 2.90 (t, J = 6.5 Hz, 2 H) 3.76 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.13-7.18 (m, 2 H) 7.20-7.26 (m, 2 H). MS ESI/APCI Dual posi: 290[M + H]⁺. Reference Example A-39

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.3 Hz, 2 H) 2.92 (t, J = 6.3 Hz, 2 H) 3.85 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.42-7.54 (m, 3 H) 8.35-8.49 (m, 2 H) 8.77 (s, 2 H). MS ESI/APCI Dual posi: 286[M + H]⁺. Reference Example A-40

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.51 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.76 (s, 2 H) 3.96 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.08-7.35 (m, 9 H). MS ESI/APCI Dual posi: 298[M + H]⁺. Reference Example A-41

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.30-1.51 (m, 2 H) 1.54-1.79 (m, 4 H) 1.80-1.93 (m, 2 H) 1.93-2.06 (m, 2 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.78-2.96 (m, 3 H) 3.77 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 8.62 (s, 2 H). MS ESI/APCI Dual posi: 292[M + H]⁺. Reference Example A-42

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.4 Hz, 2 H) 2.94 (t, J = 6.4 Hz, 2 H) 4.04 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.37-7.45 (m, 3 H) 7.65 (s, 1 H) 7.89-7.93 (m, 2 H). MS ESI/APCI Dual posi: 291[M + H]⁺. Reference Example A-43

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.75-1.80 (m, 4 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.71-2.77 (m, 4 H) 2.90 (t, J = 6.5 Hz, 2 H) 3.72 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.91-7.05 (m, 3 H). MS ESI/APCI Dual posi: 262[M + H]⁺.

TABLE 18-7 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-44

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.2 Hz, 3 H) 2.33 (s, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.76 (s, 2 H) 4.14 (q, J = 7.2 Hz, 2 H) 7.09-7.17 (m, 2 H) 7.17-7.24 (m, 2 H). MS ESI/APCI Dual posi: 222[M + H]⁺. Reference Example A-45

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.0 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 3.80 (s, 3 H) 4.14 (q, J = 7.0 Hz, 2 H) 6.79-6.91 (m, 2 H) 7.17-7.30 (m, 2 H). MS ESI/APCI Dual posi: 238[M + H]⁺. Reference Example A-46

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.19 (t, J = 7.1 Hz, 3 H) 2.61 (dd, J = 15.6, 5.3 Hz, 1 H) 2.72 (dd, J = 15.6, 8.8 Hz, 1 H) 3.54 (d, J = 13.1 Hz, 1 H) 3.66 (d, J = 13.1 Hz, 1 H) 4.01- 4.18 (m, 3 H) 7.13-7.44 (m, 10 H). MS ESI/APCI Dual posi: 284[M + H]⁺. Reference Example A-47

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J = 7.1 Hz, 3 H) 2.63 (dd, J = 15.5, 5.3 Hz, 1 H) 2.74 (dd, J = 15.5, 8.8 Hz, 1 H) 3.59 (d, J = 13.5 Hz, 1 H) 3.70 (d, J = 13.5 Hz, 1 H) 4.02- 4.21 (m, 3 H) 7.25-7.48 (m, 10 H) 7.48-7.64 (m, 4 H). MS ESI/APCI Dual posi: 360[M + H]⁺. Reference Example A-48

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J = 7.0 Hz, 3 H) 1.28-1.71 (m, 6 H) 1.77-2.03 (m, 2 H) 2.61-2.76 (m, 1 H) 3.03 (dt, J = 6.7, 3.5 Hz, 1 H) 3.76 (d, J = 13.3 Hz, 1 H) 3.89 (d, J = 13.3 Hz, 1 H) 4.02-4.23 (m, 2 H) 7.27-7.49 (m, 5 H) 7.49-7.64 (m, 4 H). MS ESI/APCI Dual posi: 338[M + H]⁺. Reference Example A-49

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.01-1.61 (m, 7 H) 1.62-1.86 (m, 2 H) 1.86-2.02 (m, 1 H) 2.08-2.36 (m, 2 H) 2.69-2.93 (m, 1 H) 3.75 (d, J = 13.3 Hz, 1 H) 3.92 (d, J = 13.3 Hz, 1 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.26-7.48 (m, 5 H) 7.49-7.63 (m, 4 H). MS ESI/APCI Dual posi: 338[M + H]⁺. Reference Example A-50

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.14-1.35 (m, 6 H) 2.44-2.72 (m, 4 H) 2.83-2.97 (m, 2 H) 3.77 (s, 2 H) 4.14 (q, J = 7.0 Hz, 2 H) 7.09-7.30 (m, 4 H). MS ESI/APCI Dual posi: 236[M + H]⁺.

TABLE 18-8 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-51

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.55 (t, J = 6.4 Hz, 2 H) 2.92 (t, J = 6.4 Hz, 2 H) 4.03 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.73-7.84 (m, 1 H) 7.84-7.97 (m, 2 H). MS ESI/APCI Dual posi: 344[M + H]⁺. Reference Example A-52

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.31 (s, 9 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 3.77 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.21-7.29 (m, 2 H) 7.30-7.39 (m, 2 H). MS ESI/APCI Dual posi: 264[M + H]⁺. Reference Example A-53

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.93 (t, J = 6.5 Hz, 2 H) 3.97 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.30-7.38 (m, 1 H) 7.49-7.57 (m, 1 H) 7.60-7.68 (m, 2 H). MS ESI/APCI Dual posi: 276[M + H]⁺. Reference Example A-54

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (t, J = 7.1 Hz, 3 H) 2.95 (dd, J = 12.0, 6.5 Hz, 1 H) 3.31 (dd, J = 12.0, 8.6 Hz, 1 H) 3.74-3.92 (m, 3 H) 4.02-4.27 (m, 2 H) 7.22-7.38 (m, 8 H) 7.39-7.47 (m, 2 H) 7.50-7.61 (m, 4 H). MS ESI/APCI Dual posi: 360[M + H]⁺. Reference Example A-55

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.90 (t, J = 6.4, Hz, 2 H) 3.86 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.39-7.47 (m, 1 H) 7.47-7.56 (m, 2 H) 7.60 (s, 1 H). MS ESI/APCI Dual posi: 276[M + H]⁺. Reference Example A-56

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.3 Hz, 2 H) 2.90 (t, J = 6.3 Hz, 2 H) 3.93 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.76 (s, 1 H) 7.82 (s, 2 H). MS ESI/APCI Dual posi: 344[M + H]⁺. Reference Example A-57

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.22-2.36 (m, 6 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 6.91-7.01 (m, 2 H) 7.16 (d, J = 8.4 Hz, 1 H). MS ESI/APCI Dual posi: 236[M + H]⁺.

TABLE 18-9 Compound Salt No. Structure Analytical Data information Reference Example A-58

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.78 (s, 2 H) 3.81 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.76-6.82 (m, 1 H) 6.87- 6.93 (m, 2 H) 7.19-7.25 (m, 1 H). MS ESI/APCI Dual posi: 238[M + H]⁺. Reference Example A-59

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.33 (s, 3 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 3.71 (s, 2 H) 3.78 (s, 3 H) 4.13 (q, J = 7.1 Hz, 2 H) 6.63- 6.76 (m, 2 H) 7.18 (d, J = 8.4 Hz, 1 H). MS ESI/APCI Dual posi: 252[M + H]⁺. Reference Example A-60

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J = 7.1 Hz, 3 H) 1.29-1.75 (m, 10 H) 2.50 (s, 2 H) 3.74 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.42-7.64 (m, 4 H). MS ESI/APCI Dual posi: 344[M + H]⁺. Reference Example A-61

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.55 (ddd, J = 13.7, 10.9, 4.4 Hz, 2 H) 2.00-2.18 (m, 2 H) 2.70 (s, 2 H) 3.49 (ddd, J = 11.8, 10.9, 2.4 Hz, 2 H) 3.73- 3.87 (m, 4 H) 4.19 (q, J = 7.1 Hz, 2 H) 7.41 (2, J = 8.1 Hz, 2 H) 7.56 (d, J = 8.1 Hz, 2 H). MS ESI/APCI Dual posi: 346[M + H]⁺. Reference Example A-62

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.40-2.57 (m, 5 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.76 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.16-7.30 (m, 4 H). MS ESI/APCI Dual posi: 254[M + H]⁺. Reference Example A-63

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.78 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.18-7.25 (m, 3 H) 7.33 (s, 1 H). MS ESI/APCI Dual posi: 242[M + H]⁺. Reference Example A-64

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.51 (t, J = 6.5 Hz, 2 H) 2.86 (t, J = 6.5 Hz, 2 H) 3.76 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.16 (dd, J = 8.4, 2.2 Hz, 1 H) 7.38 (d, J = 8.4 Hz, 1 H) 7.44 (d, J = 2.2 Hz, 1 H). MS ESI/APCI Dual posi: 276[M + H]⁺.

TABLE 18-10 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-65

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.3 Hz, 2 H) 2.89 (t, J = 6.3 Hz, 2 H) 3.82 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.06-7.14 (m, 1 H) 7.18-7.35 (m, 3 H). MS ESI/APCI Dual posi: 292[M + H]⁺. Reference Example A-66

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.89 (t, J = 6.4 Hz, 2 H) 3.80 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.13-7.19 (m, 2 H) 7.32-7.37 (m, 2 H). MS ESI/APCI Dual posi: 292[M + H]⁺. Reference Example A-67

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.35 (s, 3 H) 2.51 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.84 (d, J = 8.5 Hz, 1 H) 6.97-7.04 (m, 2 H) 7.19 (d, J = 8.1 Hz, 2 H) 7.67 (dd, J = 8.5, 2.4 Hz, 1 H) 8.09 (d, J = 2.4 Hz, 1 H). MS ESI/APCI Dual posi: 315[M + H]⁺. Reference Example A-68

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.40 (t, J = 7.0 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.73 (s, 2 H) 4.02 (q, J = 7.0 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.82-6.88 (m, 2 H) 7.19-7.24 (m, 2 H). MS ESI/APCI Dual posi: 252[M + H]⁺. Reference Example A-69

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.88 (t, J = 6.4 Hz, 2 H) 3.76 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.87 (d, J = 8.3 Hz, 1 H) 7.08- 7.23 (m, 3 H) 7.35-7.43 (m, 2 H) 7.69 (dd, J = 8.3, 2.5 Hz, 1 H) 8.11 (d, J = 2.5 Hz, 1 H). MS ESI/APCI Dual posi: 301[M + H]⁺. Reference Example A-70

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.2 Hz, 3 H) 2.54 (t, J = 6.4 Hz, 2 H) 2.93 (t, J = 6.4 Hz, 2 H) 3.86 (s, 2 H) 4.15 (q, J = 7.2 Hz, 2 H) 7.36-7.51 (m, 3 H) 7.67-7.79 (m, 2 H) 7.91-8.04 (m, 2 H) 8.62 (s, 1 H). MS ESI/APCI Dual posi: 285[M + H]⁺. Reference Example A-71

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.3 Hz, 2 H) 2.88 (t, J = 6.3 Hz, 2 H) 3.82 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.42-7.46 (m, 2 H) 7.67 (s, 1 H). MS ESI/APCI Dual posi: 310[M + H]⁺.

TABLE 18-11 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-72

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.44 (d, J = 6.4 Hz, 2 H) 2.78 (dd, J = 13.5, 6.8 Hz, 1 H) 2.89 (dd, J = 13.5, 6.5 Hz, 1 H) 3.20-3.40 (m, 1 H) 3.86 (s, 2 H) 4.01-4.22 (m, 2 H) 7.13-7.37 (m, 7 H) 7.38-7.64 (m, 7 H). MS ESI/APCI Dual posi: 374 [M + H]⁺, 396 [M + Na]⁺. Reference Example A-73

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.70-1.96 (m, 2 H) 2.53 (d, J = 6.2 Hz, 2 H) 2.72 (t, J = 7.9 Hz, 2 H) 3.00-3.18 (m, 1 H) 3.70-3.93 (m, 2 H) 4.14 (q, J = 7.2 Hz, 2 H) 7.08-7.68 (m, 14 H). MS ESI/APCI Dual posi: 388 [M + H]⁺, 410 [M + Na]⁺. Reference Example A-74

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J = 6.4 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.39 (dd, J = 15.2, 6.0 Hz, 1 H) 2.51 (dd, J = 15.2, 6.8 Hz, 1 H) 3.09-3.27 (m, 1 H) 3.74-3.96 (m, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.21 (ddd, J = 6.2, 4.9, 2.4 Hz, 1 H) 7.44 (d, J = 8.1 Hz, 2 H) 7.68-7.76 (m, 2 H) 7.91- 7.99 (m, 2 H) 8.68 (dt, J = 4.9, 1.3 Hz, 1 H). MS ESI/APCI Dual posi: 299 [M + H]⁺, 321 [M + Na]⁺. Reference Example A-75

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J = 6.4 Hz, 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.31-2.55 (m, 2 H) 3.04-3.23 (m, 1 H) 3.82-3.90 (m, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.38- 7.50 (m, 2 H) 7.52-7.65 (m, 2 H). MS ESI/APCI Dual posi: 290 [M + H]⁺. MS ESI/APCI Dual nega: 324 [m + Cl]⁻. Reference Example A-76

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15 (d, J = 6.4 Hz, 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.29-2.42 (m, 4 H) 2.49 (dd, J = 15.0, 6.7 Hz, 1 H) 3.04-3.24 (m, 1 H) 3.64-3.86 (m, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.07-7.16 (m, 2 H) 7.17-7.25 (m, 2 H). MS ESI/APCI Dual posi: 236 [M + H]⁺, 258 [M + Na]⁺. Reference Example A-77

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.99-1.20 (m, 5 H) 1.27 (t, J = 7.1 Hz, 3 H) 1.38-1.76 (m, 5 H) 1.83-1.99 (m, 3 H) 2.25-2.40 (m, 1 H) 2.40-2.59 (m, 4 H) 2.99-3.14 (m, 1 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.14-7.33 (m, 5 H). MS ESI/APCI Dual posi: 304 [M + H]⁺. Reference Example A-78

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.51 (dd, J = 15.5, 9.6 Hz, 1 H) 2.71 (dd, J = 15.5, 4.0 Hz, 1 H) 3.56-3.76 (m, 1 H) 3.92 (d, J = 13.0 Hz, 1 H) 3.98-4.27 (m, 3 H) 7.28-7.49 (m, 5 H) 7.49-7.66 (m, 4 H). MS ESI/APCI Dual posi: 352 [M + H]⁺.

TABLE 18-12 Compound Salt No. Structure Analytical Data information Reference Example A-79

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14-1.81 (m, 11 H) 1.98-2.12 (m, 2 H) 2.65 (s, 2 H) 3.82 (s, 2 H) 4.15 (q, J = 7.1 Hz. 2 H) 7.41 (d, J = 8.1 Hz, 2 H) 7.56 (d, J = 8.1 Hz, 2 H). MS ESI/APCI Dual posi: 344[M + H]⁺, 366[M + Na]⁺. Reference Example A-80

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.86-2.00 (m, 4 H) 2.34-2.50 (m, 2 H) 2.89 (s, 2 H) 3.86 (s, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 7.44 (d, J = 8.1 Hz, 2H) 7.57 (d, J = 8.1 Hz, 2H). MS ESI/APCI Dual posi: 316[M + H]⁺, 338[M + Na]⁺. Reference Example A-81

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.29-1.52 (m, 6 H) 1.58-1.73 (m, 4 H) 2.33 (s, 3 H) 2.51 (s, 2 H) 3.63 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.12 (d, J = 7.9 Hz, 2 H) 7.18-7.38 (m, 2 H). MS ESI/APCI Dual posi: 290[M + H]⁺. Reference Example A-82

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21-1.29 (m, 9 H) 2.50 (s, 2 H) 3.78 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.45-7.59 (m, 4 H). MS ESI/APCI Dual posi: 304[M + H]⁺. Reference Example A-83

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13-1.62 (m, 11 H) 1.96-2.12 (m, 2 H) 2.33 (s, 3 H) 2.64 (s, 2 H) 3.72 (s, 2 H) 4.15 (q, J = 7.0 Hz, 2 H) 7.08-7.14 (m, 2 H) 7.14-7.20 (m, 2 H). MS ESI/APCI Dual posi: 290[M + H]⁺, 312[M + Na]⁺. Reference Example A-84

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 8 H) 1.71 (dd, J = 6.2, 4.2 Hz, 4 H) 2.59 (s, 2 H) 3.60-3.77 (m, 7 H) 3.84-4.01 (m, 2 H) 7.38-7.65 (m, 8 H), MS ESI/APCI Dual posi: 396[M + H]⁺, 418[M + Na]⁺. Reference Example A-85

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15-1.31 (m, 9 H) 2.32 (s, 3 H) 2.50 (s, 2 H) 3.67 (s, 2 H) 4.14 (q. J = 7.1 Hz, 2 H) 7.11 (d, J = 7.8 Hz, 2 H) 7.23 (d, J = 7.8 Hz, 2 H). MS ESI/APCI Dual posi: 250[M + H]⁺.

TABLE 18-13 Compound Salt No Structure Analytical Data information Reference Example A-86

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.46-1.62 (m, 2 H) 1.98-2.14 (m, 2 H) 2.33 (s, 3 H) 2.70 (s, 2 H) 3.48 (ddd, J = 11.9, 10.7, 2.3 Hz, 2 H) 3.72 (s, 2 H) 3.79 (dt, J = 11.9, 4.0 Hz, 2 H) 4.19 (q, J = 7.1 Hz, 2 H) 7.06-7.21 (m, 4 H). MS ESI/APCI Dual posi: 292[M + H]⁺, 314[M + Na]⁺. Reference Example A-87

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.85-1.99 (m, 4 H) 2.33 (s, 3 H) 2.35-2.47 (m, 2 H) 2.89 (s, 2 H) 3.76 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.09-7.15 (m, 2 H) 7.16-7.22 (m, 2 H). MS ESI/APCI Dual posi: 262[M + H]⁺, 284[M + Na]⁺. Reference Example A-88

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12-1.62 (m, 11 H) 1.95-2.12 (m, 2 H) 2.71 (s, 2 H) 3.99 (s, 2 H) 4.17 (q, J = 6.9 Hz, 2 H) 7.36-7.50 (m, 3 H) 7.55-7.68 (m, 1 H) 7.84-8.02 (m, 2 H). MS ESI/APCI Dual posi: 359[M + H]⁺, 381[M + Na]⁺. Reference Example A-89

¹H NMR (300 MHz. CHLOROFORM-d) δ ppm 1.16 (d, J = 7.0 Hz, 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.33 (s, 3 H) 2.55-2.75 (m, 2 H) 2.79-2.95 (m, 1 H) 3.75 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.10-7.22 (m, 4 H). MS ESI/APCI Dual posi: 236[M + H]⁺, 258[M + Na]⁺. Reference Example A-90

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J = 6.8 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.54-2.77 (m, 2 H) 2.82-2.98 (m, 1 H) 3.86 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.22 (ddd, J = 6.3, 4.9, 2.3 Hz, 1 H) 7.42 (d, J = 8.4 Hz, 2 H) 7.69-7.76 (m, 2 H) 7.95 (d, J = 8.4 Hz, 2 H) 8.64-8.72 (m, 1 H). MS ESI/APCI Dual posi: 299[M + H]⁺, 321[M + Na]⁺. Reference Example A-91

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J = 6.4 Hz, 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.30-2.54 (m, 2 H) 3.11-3.29 (m, 1 H) 3.96-4.20 (m, 4 H) 7.37-7.44 (m, 3 H) 7.64 (s, 1 H) 7.87-7.94 (m, 2 H). MS ESI/APCI Dual posi: 305[M + H]⁺, 327[M + Na]⁺. MS ESI/APCI Dual nega: 303[M − H]⁻. Reference Example A-92

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 1.83-2.01 (m, 4 H) 2.33-2.52 (m, 2 H) 2.95 (s, 2 H) 4.04 (d, J = 0.9 Hz, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 7.36-7.52 (m, 3 H) 7.62-7.66 (m, 1 H) 7.86-7.98 (m, 2 H). MS ESI/APCI Dual Posi: 331[M + H]⁺, 353[M + Na]⁺.

TABLE 18-14 Compound Salt No. Structure Analytical Data information Reference Example A-93

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.34 (m, 9 H) 2.49 (s, 2 H) 3.98 (d, J = 0.9 Hz, 2 H) 4.16 (q, J = 7.0 Hz, 2 H) 7.38-7.47 (m, 3 H) 7.66 (s, 1 H) 7.86-7.95 (m, 2 H). MS ESI/APCI Dual posi: 319[M + H]⁺, 341[M + Na]⁺. Reference Example A-94

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.49-1.62 (m, 2 H) 2.03-2.13 (m, 2 H) 2.76 (s, 2 H) 3.49 (ddd, J = 11.8, 11.0, 2.4 Hz, 2 H) 3.80 (dt, J = 11.8, 4.2 Hz, 2 H) 4.00 (d, J = 0.8 Hz, 2 H) 4.21 (q, J = 7.1 Hz, 2 H) 7.36- 7.50 (m, 3 H) 7.62 (s, 1 H) 7.82-7.97 (m, 2 H). MS ESI/APCI Dual Posi: 361[M + H]⁺, 383[M + Na]⁺. Reference Example A-95

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.64-1.76 (m, 4 H) 2.56 (s, 2 H) 3.55-3.78 (m, 5 H) 3.83-3.98 (m, 4 H) 7.35-7.50 (m, 3 H) 7.67 (s, 1 H) 7.86-8.00 (m, 2 H). MS ESI/APCI Dual posi: 347[M + H]⁺, 369[M + Na]⁺. Reference Example A-96

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.01-1.21 (m, 2 H) 1.38-1.57 (m, 3 H) 1.62 (dd, J = 6.2, 4.4 Hz, 4 H) 1.87-2.03 (m, 4 H) 2.36 (d, J = 6.2 Hz, 2 H) 2.41-2.61 (m, 3 H) 3.48-3.75 (m, 5 H) 3.77-3.99 (m, 2 H) 7.09-7.37 (m, 5 H). MS ESI/APCI Dual posi: 346[M + H]⁺, 368[M + Na]⁺. Reference Example A-97

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18 (d, J = 6.4 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.35-2.58 (m, 2 H) 3.13-3.26 (m, 1 H) 3.65-3.95 (m, 2 H) 4.15 (g, J = 7.1 Hz, 2 H) 7.41-7.47 (m, 2 H) 7.53-7.58 (m, 2 H) 7.63-7.77 (m, 4 H). MS ESI/APCI Dual posi: 366[M + H]⁺, 388[M + Na]⁺. Reference Example A-98

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.62 (m, 11 H) 1.96-2.21 (m, 2 H) 2.67 (s, 2 H) 3.82 (s, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 7.18-7.25 (m, 1 H) 7.39 (d, J = 8.5 Hz, 2 H) 7.68-7.74 (m, 2 H) 7.94 (d, J = 8.4 Hz, 2 H) 8.62-8.74 (m, 1 H). MS ESI/APCI Dual posi: 353[M + H]⁺, 375[M + Na]⁺. Reference Example A-99

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.62 (m, 11 H) 1.96-2.21 (m, 2 H) 2.67 (s, 2 H) 3.82 (s, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 7.18-7.25 (m, 1 H) 7.39 (d, J = 8.5 Hz, 2 H) 7.68-7.74 (m, 2 H) 7.94 (d, J = 8.4 Hz, 2 H) 8.62-8.74 (m, 1 H). MS ESI/APCI Dual posi: 353[M+ H]⁺, 375[M + Na]⁺.

TABLE 18-15 Compound Salt No. Structure Analytical Data information Reference Example A-100

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J = 6.7 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.53-2.76 (m, 2 H) 2.80-2.96 (m, 1 H) 3.86 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.41-7.46 (m, 2 H) 7.54-7.60 (m, 2 H). MS ESI/APCI Dual posi: 290[M + H]⁺, 312[M + Na]⁺. Reference Example A-101

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18 (d, J = 7.0 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.56-2.79 (m, 2 H) 2.81-3.01 (m, 1 H) 3.97-4.06 (m, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.39-7.48 (m, 3 H) 7.64 (s, 1 H) 7.89-7.94 (m, 2 H). MS ESI/APCI Dual posi: 305[M + H]⁺, 327[M + Na]⁺. Reference Example A-102

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.63-1.78 (m, 4 H) 2.59 (s, 2 H) 3.62-3.71 (m, 5 H) 3.75 (s, 2 H) 3.93 (dt, J = 11.9, 6.2 Hz, 2 H) 7.18-7.25 (m, 1 H) 7.49 (d, J = 8.2 Hz, 2 H) 7.65-7.81 (m, 2 H) 7.96 (d, J = 8.2 Hz, 2 H) 8.63-8.73 (m, 1 H). MS ESI/APCI Dual posi: 341[M + H]⁺, 363[M + Na]⁺. Reference Example A-103

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.61-1.77 (m, 4 H) 2.57 (s, 2 H) 3.61-3.71 (m, 5 H) 3.74 (s, 2 H) 3.82-3.99 (m, 2 H) 7.48-7.54 (m, 2 H) 7.55-7.61 (m, 2 H). MS ESI/APCI Dual posi: 332[M + H]⁺, 354[M + Na]⁺. Reference Example A-104

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.99-2.40 (m, 15 H) 2.39-2.97 (m, 6 H) 4.09-4.22 (m, 2 H) 7.11-7.35 (m, 5 H). MS ESI/APCI Dual posi: 304[M + H]⁺. Reference Example A-105

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.19 (d, J = 6.8 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.56-2.76 (m, 2 H) 2.83-3.00 (m, 1 H) 3.85 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.37-7.46 (m, 2 H) 7.52-7.59 (m, 2 H) 7.64-7.72 (m, 4 H). MS ESI/APCI Dual posi: 366[M + H]⁺, 388[M + Na]⁺. Reference Example A-106

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22-1.29 (m, 9 H) 2.53 (s, 2 H) 3.78 (s, 2 H) 4.15 (q, j = 7.1 Hz, 2 H) 7.18-7.25 (m, 1 H) 7.43-7.48 (m, 2 H) 7.68-7.75 (m, 2 H) 7.94 (d, J = 8.2 Hz, 2 H) 8.64-8.71 (m, 1 H). MS ESI/APCI Dual posi: 313[M + H]⁺, 335[M + Na]⁺.

TABLE 18-16 Compound Salt No. Structure Analytical Data information Reference Example A-107

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.44-1.64 (m, 2 H) 1.99-2.16 (m, 2 H) 2.72 (s, 2 H) 3.49 (ddd, J = 11.8, 10.9, 2.4 Hz, 2 H) 3.74-3.86 (m, 4 H) 4.21 (q, J = 7.1 Hz, 2 H) 7.19-7.25 (m, 1 H) 7.39 (d, J = 8.3 Hz, 2 H) 7.66-7.81 (m, 2 H) 7.94 (d, J = 8.3 Hz, 2 H) 8.63-8.72 (m, 1 H). MS ESI/APCI Dual posi: 355[M + H]⁺, 377[M + Na]⁺. Reference Example A-108

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12-1.77 (m, 13 H) 2.53 (s, 2 H) 3.75 (s, 2 H) 4.14 (q, J = 7.2 Hz, 2 H) 7.21 (ddd, J = 6.1, 4.8. 2.4 Hz, 1 H) 7.49 (d, J = 8.5 Hz, 2 H) 7.65-7.79 (m, 2 H) 7.86-8.00 (m, 2 H) 8.60-8.72 (m, 1 H). MS ESI/APCI Dual posi: 353[M + H]⁺, 375[M + Na]⁺. Reference Example A-109

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.76 (m, 13 H) 2.48 (s, 2 H) 3.94 (s, 2 H) 4.15 (q, J = 7.1 Hz. 2 H) 7.32-7.50 (m, 3 H) 7.66 (s, 1 H) 7.85-7.96 (m, 2 H). MS ESI/APCI Dual posi: 359[M + H]⁺, 381[M + Na]⁺. MS ESI/APCI Dual nega: 357[M − H]⁻. Reference Example A-110

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.3 Hz, 2 H) 2.88 (t, J = 6.3 Hz, 2 H) 3.86 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.16-7.25 (m, 2 H) 7.50-7.58 (m, 1 H). MS ESI/APCI Dual posi : 294[M + H]⁺, 316[M + Na]⁺. Reference Example A-111

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.92-1.17 (m, 2 H) 1.28 (t, J = 7.1 Hz, 3 H) 1.33-1.77 (m, 3 H) 1.79-2.05 (m, 8 H) 2.31-2.56 (m, 5 H) 2.92 (s, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 7.09-7.38 (m, 5 H). MS ESI/APCI Dual posi: 330[M + H]⁺. Reference Example A-112

¹H NMR (300 MHz, CHLOROF0RM-d) δ ppm 1.02-1.19 (m, 8 H) 1.27 (t, J = 7.1 Hz, 3 H) 1.38-1.64 (m, 3 H) 1.84-2.03 (m, 4 H) 2.33-2.57 (m, 5 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.11-7.37 (m, 5 H). MS ESI/APCI Dual posi: 318[M + H]⁺. Reference Example A-113

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1Hz, 3 H) 2.53 (t, J = 6.3 Hz, 2 H) 2.89 (d, J = 6.3 Hz, 2 H) 3.90 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.30 (d, J = 9.8 Hz, 1 H) 7.39 (d, J = 7.5 Hz, 1 H) 7.49-7.57 (m, 1 H). MS ESI/APCI Dual posi: 294[M + H]⁺, 316[M + Na]⁺.

TABLE 18-17 Compound Salt No. Structure Analytical Data information Reference Example A-114

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.92-1.16 (m, 2 H) 1.20-1.33 (m, 3 H) 1.35-1.71 (m, 3 H) 1.79-1.97 (m, 4 H) 1.97-2.18 (m, 4 H) 2.38-2.55 (m, 3 H) 2.67-2.79 (m, 2 H) 3 38-3.58 (m, 2 H) 3.73-3.89 (m, 2 H) 4-06-4.29 (m, 2 H) 7.09-7.38 (m, 5 H). MS ESI/APCI Dual posi: 360[M + H]⁺, 382[M + Na]⁺. Reference Example A-115

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24-1.30 (m, 9 H) 2.53 (s, 2 H) 3.78 (s, 2 H) 4.16 (q, J = 7.0 Hz, 2 H) 7.43-7.50 (m, 2 H) 7.52-7.57 (m, 2 H) 7.66-7.68 (m, 4 H). MS ESI/APCI Dual posi: 380[M + H]⁺, 402[M + Na]⁺. Reference Example A-116

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 1.43-1.66 (m, 2 H) 2.00-2.18 (m, 2 H) 2.75 (s, 2 H) 3.42- 3.56 (m, 2 H) 3.75-3.86 (m, 4 H) 4.21 (q, J = 7.1 Hz, 2 H) 7.39 (d, J = 8.3 Hz, 2 H) 7.55 (d, J = 8.3 Hz, 2 H) 7.60-7.77 (m, 4 H). MS ESI/APCI Dual posi: 422[M + H]⁺, 444[M + Na]⁺. Reference Example A-117

¹H NMR (300 MHz, CHLOROFORM-d δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.1 Hz, 2 H) 2.89 (t, J = 6.1 Hz, 2 H) 3.92 (s, 2 H); 4.16 (q, J = 7.1 Hz, 2 H) 7.66 (d, J = 7.8 Hz, 1 H) 7.75-7.89 (m, 2 H). MS ESI/APCI Dual posi: 344[M + H]⁺, 366[M + Na]⁺. MS ESI/APCI Dual nega: 378[M + Cl]⁻. Reference Example A-118

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.72-1.95 (m, 2 H) 1.95-2.16 (m, 4 H) 2.32 (s, 3 H) 2.72 (s, 2 H) 3.65 (s, 2 H) 3.68 (s, 3 H) 7.07-7.15 (m, 2 H) 7.19-7.25 (m, 2 H). MS ESI/APCI Dual posi: 248[M + H]⁺, 270[M + Na]⁺. Reference Example A-119

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.74-1 .96 (m, 2 H) 1.96-2.15 (m, 4 H) 2.73 (s, 2 H) 3.68 (s, 3 H) 3.76 (s, 2 H) 7.40-7.52 (m, 2 H) 7.52-7.62 (m, 2 H). MS ESI/APCI Dual posi: 302[M + H]⁺, 324[M + Na]⁺. Reference Example A-120

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.97 (s, 2 H) 4.09-4.13 (m, 2 H) 4.18 (q, J = 7.1 Hz, 2 H) 4.55 (d, J = 6.9 Hz, 2 H) 4.69 (d, J = 6.9 Hz, 2 H) 7.35-7.49 (m, 3 H) 7.68 (s, 1 H) 7.84-7.97 (m, 2 H). MS ESI/APCI Dual posi: 333[M + H]⁺, 355[M + Na]⁺. MS ESI/APCI Dual nega: 331[M −H]⁻.

TABLE 18-18 Compound Salt No. Structure Analytical Data information Reference Example A-121

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.96 (s, 2 H) 3.92 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 4.54 (d, J = 6.9 Hz, 2 H) 4.68 (d, J = 6.9 Hz, 2 H) 7.43-7.52 (m, 2 H) 7.53-7.65 (m, 2 H). MS ESI/APCI Dual posi: 318[M + H]⁺. Reference Example A-122

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.55 (t, J = 6.4 Hz, 2 H) 2.92 (t, J = 6.4 Hz, 2 H) 3.84 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.10-7.20 (m, 2 H) 7.34-7.49 (m, 4 H) 7.49-7.62 (m, 2 H). MS ESI/APCI Dual posi: 302[M + H]⁺, 324[M + Na]⁺. Reference Example A-123

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.55 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.89 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.08-7.17 (m, 2 H) 7.19-7.32 (m, 2 H) 7.34-7.46 (m, 1 H) 7.46-7.58 (m, 2 H). MS ESI/APCI Dual posi: 320[M + H]⁺, 342[M + Na]⁺. Reference Example A-124

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.55 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.89 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.23-7.48 (m, 6 H) 7.53-7.60 (m, 2 H). MS ESI/APCI Dual posi: 302[M + H]⁺, 324[M + Na]⁺. Reference Example A-125

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.3 Hz, 2 H) 2.88 (t, J = 6.3 Hz, 2 H) 3.84 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.29-7.36 (m, 1 H) 7.51 (s, 1 H) 7.63 (d, J = 7.9 Hz, 1H). MS ESI/APCI Dual posi: 310[M + H]⁺, 332[M +Na]⁺. Reference Example A-126

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1Hz, 3 H) 2.46 (s, 3 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2H) 3.81 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.23 (d, J = 7.6 Hz, 1 H) 7.38 (d, J = 7.6 Hz, 1 H) 7.56 (s, 1 H). MS ESI/APCI Dual posi: 290[M + H]⁺, 312[M + Na]⁺. Reference Example A-127

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.77-1.97 (m, 2 H) 1.98-2.18 (m, 4 H) 2.75 (s, 2 H) 3.70 (s, 3 H) 3.76 (s, 2 H) 7.21 (ddd, J = 6.3, 4.8, 2.4 Hz, 1 H) 7.40-7.51 (m, 2 H) 7.67-7.80 (m, 2 H) 7.89-7.99 (m, 2 H) 8.63-8.73 (m, 1 H). MS ESI/APCI Dual posi: 311[M + H]⁺.

TABLE 18-19 Compound Salt No. Structure Analytical Data information Reference Example A-128

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.78-1.94 (m, 2 H) 1.96-2.18 (m, 4 H) 2.72 (s, 2 H) 3.71 (s, 3 H) 3.88-4.00 (m, 2 H) 7.34-7.49 (m, 3 H) 7.62-7.69 (m, 1 H) 7.85-7.97 (m, 2H). MS ESI/APCI Dual posi: 317[M + H]⁺, 339[M + Na]⁺. MS ESI/APCI Dual nega: 315[M − H]⁻. Reference Example A-129

¹H NMR (300 MHz. CHLOROFORM-d) δ ppm 1.04-1.20 (m, 2 H) 1.27 (t, J = 7.1 Hz, 3 H) 1.37-1.59 (m, 3 H) 1.85-2.00 (m, 4 H) 2.38-2.56 (m, 3 H) 2.90 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 4.51 (d, J = 6.8 Hz, 2 H) 4.63 (d, J = 6.8 Hz, 2 H) 7.15-7.23 (m, 3 H) 7.23-7.33 (m, 2 H). MS ESI/APCI Dual posi: 332[M + H]⁺. Reference Example A-130

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.99 (s, 2 H) 3.91 (s, 2 H) 4.17 (q, J = 7.7 Hz, 2 H) 4.56 (d, J = 6.7 Hz, 2 H) 4.71 (d, J = 6.7 Hz, 2 H) 7.42-7.51 (m, 2 H) 7.50-7.60 (m, 2 H) 7.68 (s, 4 H). MS ESI/APCI Dual posi: 394IM + H]⁺. Reference Example A-131

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.3 Hz, 2 H) 2.89 (t, J = 6.3 Hz, 2 H) 3.93 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.15-7.41 (m, 2 H). MS ESI/APCI Dual posi: 312[M + H]⁺, 334[M + Na]⁺. MS ESI/APCI Dual nega: 346[M + Cl]⁻. Reference Example A-132

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.88 (t, J = 6.4 Hz, 2 H) 3.94 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.11-7.23 (m, 2 H). MS ESI/APCI Dual posi: 312[M + H]⁺, 334[M + Na]⁺. Reference Example A-133

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.89 (t, J = 6.4 Hz, 2 H) 3.80 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.67-6.12 (m, 1 H) 7.12-7.22 (m, 2 H) 7.30-7.41 (m, 2 H). MS ESI/APCI Dual posi: 324[M + H]⁺, 346[M + Na]⁺. Reference Example A-134

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.01-1.18 (m, 2 H) 1.36-1.57 (m, 3 H) 1.71-2.10 (m, 10 H) 2.38 (d, J = 6.4 Hz, 2 H) 2.40-2.55 (m, 1 H) 2.65 (s, 2 H) 3.68 (s, 3 H) 7.13-7.23 (m, 3 H) 7.24-7.32 (m, 2 R). MS ESI/APCI Dual posi: 316[M + H]⁺.

TABLE 18-20 Compound Salt No. Structure Analytical Data information Reference Example A-135

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 1.36 (s, 9 H) 2.98 (s, 2 H) 3.88 (s, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 4.55 (d, J = 6.7 Hz, 2 H) 4.70 (d, J = 6.7 Hz, 2 H) 7.37-7.49 (m, 4 H) 7.48-7.59 (m, 4 H). MS ESI/APCI Dual posi: 382[M + H]⁺ 404[M + Na]⁺. Reference Example A-136

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.0 Hz, 3 H) 2.56 (t, J = 6.4 Hz, 2 H) 2.91 (t, J = 6.4 Hz, 2 H) 3.81 (s, 2 H) 4.14 (q, J = 7.0 Hz, 2 H) 6.98-7.04 (m, 2 H) 7.27-7.32 (m, 2 H). MS ESI/APCI Dual posi: 226[M + H]⁺, 248[M + Na]⁺. Reference Example A-137

¹H NMR (600 MHz. CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.89 (t, J = 6.4 Hz, 2 H) 3.87 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.43-7.51 (m, 2 H) 7.52-7.60 (m, 2 H). MS ESI/APCI Dual posi: 326[M + H]⁺, 348[M + Na]⁺. Reference Example A-138

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.2 Hz, 3 H) 1.29-1.70 (m, 10 H) 2.50 (s, 2 H) 3.79 (s, 2 H) 4.13 (q, J = 7.2 Hz, 2 H) 7.63 (d, J = 8.3 Hz, 1 H) 7.89-7.99 (m, 1 H) 8.72 (s, 1 H). MS ESI/APCI Dual posi: 346[M + H]⁺, 367[M + Na]⁺. MS ESI/APCI Dual nega: 379[M + Cl]⁻. Reference Example A-139

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.22 (t, J = 7.0 Hz, 3 H) 1.30-1.79 (m, 10 H) 2.51 (s, 2 H) 3.95 (s, 2 H) 4.12 (q, J = 7.0 Hz, 2 H) 7.62 (d, J = 8.3 Hz, 1 H) 7.87 (dd, J = 8.3, 2.1 Hz, 1 H) 8.79 (d, J = 2.1 Hz, 1 H). MS ESI/APCI Dual posi: 345[M + H]⁺, 367[M + Na]⁺. Reference Example A-140

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.14-1.34 (m, 5 H) 1.41-1.55 (m, 2 H) 1.67-1.81 (m, 2 H) 1.89-1.99 (m, 1 H) 2.07-2.16 (m, 1 H) 2.18-2.29 (m, 1 H) 2.75 (td, J = 10.7, 3.7 Hz, 1 H) 3.78 (d, J = 13.6 Hz, 1 H) 3.93 (d, J = 13.6 Hz, 1 H) 4.09 - 4.17 (m, 2 H) 7.42 (d, J=7.8 Hz, 2 H) 7.55 (d, J=7.8 Hz, 2 H). MS ESI/APCI Dual posi: 330[M + H]⁺, 352[M + Na]+. Reference Example A-141

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J = 6.5 Hz, 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.54-2.73 (m, 2 H) 2.78-2.93 (m, 1 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.16-7.22 (m, 2 H) 7.41-7.46 (m, 2 H). MS ESI/APCI Dual posi: 300[M + H]⁺, 322[M + Na]⁺.

TABLE 18-21 Compound Salt No. Structure Analytical Data information Reference Example A-142

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.4 Hz, 2 H) 2.88 (t, J = 6.4 Hz, 2 H) 3.82 (d, J = 0.9 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.06-7.44 (m, 3 H). MS ESI/APCI Dual posi: 304 [M + H]⁺, 326[M + Na]⁺. MS ESI/APCI Dual nega: 338[M + Cl]⁻. Reference Example A-143

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.34 (d, J = 6.7 Hz, 3 H) 2.42-2.50 (m, 2 H) 2.59-2.70 (m, 1 H) 2.70-2.82 (m, 1 H) 3.84 (q, J = 6.7 Hz, 1 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.44 (d, J = 8.1 Hz. 2 H) 7.68 (d, J = 8.1 Hz, 2H). MS ESI/APCI Dual posi: 290[M + H]⁺, 312[M + Na]⁺. Reference Example A-144

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.70-0.83 (m, 2 H) 1.13-1.37 (m, 5 H) 2.69 (s, 2 H) 3.87 (s, 2 H) 4.12 (q, J = 7.0 Hz, 2 H) 7.39-7.43 (m, 2 H) 7.52-7.62 (m, 2 H). MS ESI/APCI Dual posi: 302[M + H]⁺. Reference Example A-145

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15 (d, J = 6.4 Hz. 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.37 (dd, J = 15.2, 5.9 Hz, 1 H) 2.46 (dd, J = 15.2, 7.0 Hz, 1 H) 3.02-3.23 (m, 1 H) 3.71 (d, J = 13.5 Hz, 1H) 3.79 (d. J = 13.5 Hz, 1 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.15-7.25 (m, 2 H) 7.36-7.48 (m, 2 H). Reference Example A-146

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J = 6.4 Hz, 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.39 (dd, J = 15.2, 5.8 Hz, 1 H) 2.47 (dd, J = 15.2, 7.0 Hz, 1 H) 3.04-3.23 (m, 1 H) 3.76 (d, J = 13.2 Hz, 1 H) 3.84 (d, J = 13.2 Hz, 1 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.10-7.21 (m, 2 H) 7.30-7.42 (m, 2 H). MS ESI/APCI Dual posi: 306[M + H]⁺. Reference Example A-147

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12-1.35 (m, 9 H) 2.49 (s, 2 H) 3.67 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.18-7.28 (m, 2 H) 7.38-7.48 (m, 2 H). MS ESI/APCI Dual posi: 314[M + H]⁺. Reference Example A-148

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14-1.34 (m, 9 H) 2.50 (s, 2 H) 3.72 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.10-7.20 (m, 2 H) 7.32-7.45 (m, 2 H). MS ESI/APCI Dual posi: 320[M + H]⁺.

TABLE 18-22 Compound Salt No. Structure Analytical Data information Reference Example A-149

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.3 Hz, 2 H) 2.88 (t, J = 6.3 Hz, 2 H) 3.80 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.96-7.05 (m, 2 H) 7.10 (d, J = 0.9 Hz, 1 H). MS ESI/APCI Dual posi: 288[M + H]⁺, 310[M + Na]⁺. Reference Example A-150

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.82 (t, J = 7.5 Hz, 3 H) 1.23 (d, J = 6.3 Hz, 6 H) 1.52-1.81 (m, 2 H) 2.34-2.49 (m, 2 H) 2.53-2.78 (m, 2 H) 3.57 (t, J = 6.8 Hz, 1 H) 5.01 (spt, J = 6.3 Hz, 1 H) 7.41 (d, J =8.1 Hz, 2 H) 7.57 (d, J = 8.1 Hz, 2 H). MS ESI/APCI Dual posi: 318[M + H]⁺, 340[M + Na]⁺. Reference Example A-151

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.70-1.95 (m, 2 H) 1.95-2.18 (m, 4 H) 2.72 (s, 2 H) 3.65-3.76 (m, 5 H) 7.15 (d, J = 8.4 Hz, 2 H) 7.37 (d, J = 8.4 Hz, 2 H). MS ESI/APCI Dual posi: 313[M + H]⁺, 340[M + Na]⁺. Reference Example A-152

¹H NMR (300 MHz. CHLOROFORH-d) δ ppm 1.74-1.94 (m, 2 H) 1.95-2.14 (m, 4 H) 2.71 (s, 2 H) 3.65 (s, 2 H) 3.68 (s, 3 H) 7.20-7.25 (m, 2 H) 7.40-7.45 (m, 2 H). MS ESI/APCI Dual posi: 312[M + H]⁺, 334[M + Na]⁺. Reference Example A-153

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.53-1.89 (m, 8 H) 2.62 (s, 2 H) 3.68 (s, 3 H) 3.76 (s, 2 H) 7.41-7.53 (m, 2 H) 7.51-7.60 (m, 2 H). MS ESI/APCI Dual posi: 316[M + H]⁺, 338[M + Na]⁺. Reference Example A-154

¹H NMR (300 MHz, CHLOROFORM) δ ppm 1.13-1.34 (m, 9 H) 2.50 (s, 2 H) 3.69 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.20-7.33 (m, 4 H). Reference Example A-155

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (s, 6 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.48 (s, 2 H) 3.68 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.19 (dd, J = 8.2, 2.1 Hz, 1 H) 7.36 (d, J = 8.2 Hz, 1 H) 7.48 (d, J = 2.1 Hz, 1 H). MS ESI/APCI Dual posi: 304[M + H]⁺.

TABLE 18-23 Compound Salt No. Structure Analytical Data information Reference Example A-156

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.88 (t, J = 6.4 Hz, 2 H) 3.79 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.19-7.30 (m, 2 H) 7.47 (s, 1 H). MS ESI/APCI Dual posi: 326[M + H]⁺, 348[M + Na]⁺. Reference Example A-157

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.3 Hz, 2 H) 2.87 (t, J = 6.3 Hz, 2 H) 3.80 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.19-7.24 (m, 1 H) 7.30-7.34 (m, 1 H) 7.41 (d, J = 8.2 Hz. 1 H). MS ESI/APCI Dual posi: 326[M + H]⁺, 348[M + Na]⁺. Reference Example A-158

¹H NMR (300 MHz, CHI.OROFORM-d) δ ppm 1.06-1.39 (m, 9 H) 2.50 (s, 2 H) 3.70 (s, 2 H) 4.14 (q, J = 7.0 Hz, 2 H) 6.14-6.78 (m, 1 H) 7.03-7.15 (m, 2 H) 7.33-7.37 (m, 2 H). MS ESI/APCI Dual posi: 302[M + H]⁺ , 324[M + Na]⁺. Reference Example A-159

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J = 6.5 Hz, 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.53-2.74 (m, 2 H) 2.75-2.95 (m, 1 H) 3.75 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.22-7.31 (m, 4 H). MS ESI/APCI Dual posi: 256[M + H]⁺, 278[M + Na]⁺. Reference Example A-160

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J = 6.8 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.55-2.71 (m, 2 H) 2.77-2.92 (m, 1 H) 3.74 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.15 (dd, J = 8.1, 2.1 Hz, 1 H) 7.38 (d, J = 8.1 Hz, 1 H) 7.43 (d, J = 2.1 Hz, 1 H). MS ESI/APCI Dual posi : 290[M + H]⁺, 312[M + Na]⁺. Reference Example A-161

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (s, 6 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.49 (s, 2 H) 3.70 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.19-7.32 (m, 2 H) 7.48-7.55 (m, 1 H). MS ESI/APCI Dual posi; 354[M + H]⁺. Reference Example A-162

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (s, 6 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.48 (s, 2 H) 3.72 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.22-7.28 (m, 1 H) 7.34-7.42 (m, 2 H). MS ESI/APCI Dual posi: 354[M + H]⁺.

TABLE 18-24 Compound Salt No. Structure Analytical Data information Reference Example A-163

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.76-1.94 (m, 2 H) 1.95-2.16 (m, 4 H) 2.72 (s, 2 H) 3.66 (s, 2 H) 3.68 (s, 3 H) 7.27-7.29 (m, 4 H). MS ESI/APCI Dual posi: 268[M + H]⁺, 290[M + Na]⁺. Reference Example A-164

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.72-1.92 (m, 2 H) 1.94-2.14 (m, 4 H) 2.71 (s, 2 H) 3.66 (s, 2 H) 3.69 (s, 3 H) 7.18 (dd, J = 8.2, 2.0 Hz, 1 H) 7.37 (d, J = 8.2 Hz, 1 H) 7.47 (d, J = 2.0 Hz, 1 H). MS ESI/APCI Dual posi: 302[M + H]⁺, 324[M + Na]⁺. Reference Example A-165

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.24 (s, 6 H) 1.26 (t, J = 7.0 Hz, 3 H) 1.65-1.83 (m, 3 H) 2.51 (s, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.0 Hz, 2 H) 7.39-7.46 (m, 4 H). MS ESI/APCI Dual posi: 300[M + H]⁺, 322[M + Na]⁺. Reference Example A-166

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.22 (s, 6 H) 1.26 (t, J = 7.0 Hz, 3 H) 2.49 (s, 2 H) 3.67 (s, 2 H) 3.86 (s, 3 H) 4.14 (q = 7.0 Hz, 2 H) 6.93 (d, J = 8.7 Hz, 1 H) 7.22-7.26 (m, 2 H). MS ESI/APCI Dual posi: 350[M + H]⁺, 372[M + Na]⁺. Reference Example A-167

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23 (s, 6 H) 1.26 (t, J = 7.0 Hz, 3 H) 2.28 (s, 6 H) 2.50 (s, 2 H) 3.62 (s, 2 H) 4.15 (q, J = 7.0 Hz, 2 H) 6.14-6.42 (m, 1 H) 7.04 (s, 2 H). MS ESI/APCI Dual posi: 330[M + H]⁺, 352[M + Na]⁺. Reference Example A-168

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (d, J = 6.4 Hz, 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.37 (dd, J = 15.2, 5.8 Hz, 1 H) 2.46 (dd, J = 15.2, 7.0 Hz, 1 H) 3.04-3.20 (m, 1 H) 3.72 (d, J = 13.2 Hz, 1 H) 3.80 (d, J = 13.2 Hz, 1 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.17-7.37 (m, 4 H). MS ESI/APCI Dual posi: 256[M + H]⁺. Reference Example A-169

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (d, J = 6.4 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.31-2.52 (m, 2 H) 3.05-3.15 (m, 1 H) 3.71 (d, J = 13.6 Hz, 1 H) 3.79 (d, J = 13.6 Hz, 1 H) 4.14 (q, J = 7.2 Hz, 2 H) 7.17 (dd, J = 8.2, 2.0 Hz, 1 H) 7.37 (d, J = 8.2 Hz, 1 H) 7.45 (d, J = 2.0 Hz, 1 H). MS ESI/APCI Dual posi: 290[M + H]⁺.

TABLE 18-25 Compound Salt No. Structure Analytical Data information Reference Example A-170

¹H NMR 300 MHz, CHLOROFORM-d) δ ppm 1.11-1.31 (m, 3 H) 2.50 (t, J = 6.4 Hz, 2 H) 2.76-2.98 (m, 6 H) 4.02-4.21 (m, 2 H) 7.36-7.52 (m, 4 H). MS ESI/APCI Dual posi: 290[M + H]⁺, 312[M + Na]⁺. Reference Example A-171

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.31 (m, 9 H) 2.64 (s, 2 H) 3.85 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.35-7.50 (m, 2 H) 7.49-7.64 (m, 2 H). MS ESI/APCI Dual Posi: 304[M + H]⁺, 326[M + Na]⁺. Reference Example A-172

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.15 (m, 6 H) 1.23-1.28 (m, 6 H) 3.59-3.73 (m, 3 H) 3.30 (s, 2 H) 7.44-7.51 (m, 2 H) 7.51-7.58 (m, 2 H). MS ESI/APCI Dual posi: 318[M + H]⁺, 340[M + Na]⁺. Reference Example A-173

¹H NMR (300 Mz, CHLOROFORM-d) δ ppm 1.23 (t, J = 7.1 Hz, 3 H) 3.04 (t, J = 7.0 Hz, 2 H) 3.18-3.44 (m, 6 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.39 (d, J = 7.9 Hz, 2 H) 7.59 (d, J = 7.9 Hz, 2 H). MS ESI/APCI Dual posi: 290[M + H]⁺. MS ESI/APCI Dual nesa: 324[M + Cl]⁻. Reference Example A-174

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18 (d, J = 6.4 Hz, 3 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.40 (dd, J = 15.2, 5.8 Hz, 1 H) 2.50 (dd, J = 15.2, 7.0 Hz, 1 H) 3.10-3.28 (m, 1H) 3.75-3.94 (m, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.07-7.16 (m, 2 H) 7.36-7.42 (m, 2 H) 7.46-7.57 (m, 4 H). MS ESI/APCI Dual posi: 316[M + H]⁺, 338[M + Na]⁺. Reference Example A-175

¹H NMR (300 MHz, CHLOROFORM-d) δ ppn 1.72-1.98 (m, 2 H) 1.98-2.20 (m, 4 H) 2.75 (s, 2 H) 3.70 (s, 3 H) 3.74 (s, 2 H) 7.02-7.18 (m, 2 H) 7.35-7.45 (m, 2 H) 7.45-7.60 (m, 4 H). MS ESI/APCI Dual Posi: 328[M + H]⁺, 350[M + Na]⁺. Reference Example A-176

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15-1.35 (m, 9 H) 2.24-2.31 (m, 3 H) 2.51 (s, 2 H) 3.65 (s, 2 H) 4.15 (q, J = 6.9 Hz, 2 H) 6.85-7.06 (m, 1 H) 7.06-7.24 (m, 2 H). MS ESI/APCI Dual posi: 268[M + H]⁺.

TABLE 18-26 Compound Salt No. Structure Analytical Data information Reference Example A-177

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17-1.32 (m, 9 H) 2.35 (s, 3 H) 2.50 (s, 2 H) 3.66 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.08-7.17 (m, 1 H) 7.20-7.36 (m, 2 H). MS ESI/APCI Dual posi: 284[M + H]⁺, 306[M + Na]⁺. ' Reference Example A-178

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J = 7.1 Hz, 3 H) 2.35-2.47 (m, 2 H) 2.69-2.95 (m, 2 H) 3.18-3.35 (m, 1 H) 3.86 (s, 2 H) 4.02-4.21 (m, 2 H) 7.13-7.19 (m, 2 H) 7.21-7.38 (m, 5 H) 7.48-7.58 (m, 2 H). MS ESI/APCI Dual posi: 366[M + H]⁺. Reference Example A-179

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.93 (t, J = 7.4 Hz, 3 H) 1.42-1.65 (m, 2 H) 2.35-2.56 (m, 2 H) 2.88-3.04 (m, 1 H) 3.67 (s, 3 H) 3.85 (s, 2 H) 7.43-7.49 (m, 2 H) 7.54-7.60 (m, 2 H). MS ESI/APC1 Dual posi: 290[M + H]⁺, 312[M + Na]⁺. Reference Example A-180

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.89 (t, J = 7.5 Hz, 6 H) 1.35-1.65 (m, 4 H) 2.47 (s, 2 H) 3.64-3.74 (m, 5 H) 7.38-7.65 (m, 4 H). MS ESI/APC1 Dual posi: 318[M + H]⁺, 340[M + Na]⁺. Reference Example A-181

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (s, 6 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.22-2.25 (m, 3 H) 2.49 (s, 2 H) 3.67 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.97-7.13 (m, 3 H). MS ESI/APCI Dual posi: 268[M + H]⁺. | Reference Example A-182

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J = 7.1 Hz, 3 H) 1.68-1.94 (m, 2 H) 2.42-2.60 (m, 2 H) 2.70 (t, J = 8.0 Hz, 2 H) 2.95-3.13 (m, 1 H) 3.80-3.87 (m, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.11-7.22 (m, 3 H) 7.23-7.31 (m, 2 H) 7.40-7.46 (m, 2 H) 7.53-7.59 (m, 2 H). MS ESI/APCI Dual posi: 380[M + H]⁺, 402[M + Na]⁺. Reference Example A-183

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.30 (m, 9 H) 1.96-2.12 (m, 2 H) 2.21-2.42 (m, 2 H) 2.50 (s, 2 H) 3.65 (s, 2 H) 3.93-4.06 (m, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.80-6.86 (m, 2 H) 7.23-7.29 (m, 2 H). MS ESI/APCI Dual posi: 362[M + H]⁺.

TABLE 18-27 Compound Salt No. Structure Analytical Data information Reference Example A-184

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13-1.35 (m, 9 H) 1.95-2.13 (m, 2 H) 2.14-2.44 (m, 5 H) 2.51 (s, 2 H) 3.62 (s, 2 H) 3.91-4.07 (m, 2 H) 4.14 (q, J = 7.2 Hz, 2 H) 6.63-6.83 (m, 1 H) 7.01-7.20 (m, 2 H). MS ESI/APCI Dual posi: 376[M + H]⁺. Reference Example A-185

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12-1.36 (m, 9 H) 2.49 (s, 2 H) 3.65 (s, 2 H) 4.15 (q, J = 7.3 Hz, 2 H) 4.48-4.68 (m, 5 H) 6.99-7.10 (m, 1 H) 7.17-7.25 (m, 1 H) 7.39-7.45 (m, 1 H). MS ESI/APCI Dual posi: 364[M + H]⁺, 386[M + Na]⁺. Reference Example A-186

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15-1.35 (m, 9 H) 2.22 (s, 3 H) 2.51 (s, 2 H) 3.63 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.50-4.68 (m, 5 H) 6.80-6.85 (m, 1 H) 7.09-7.18 (m, 2 H). MS ESI/APCI Dual posi: 344[M + H]⁺, 366[M + Na]⁺. MS ESI/APCI Dual nega: 342[M − H]⁻, 378[M + C1]⁻. Reference Example A-187

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.70-0.83 (m, 2 H) 0.96-1.07 (m, 2 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.10-2.27 (m, 1 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.87 (t, J = 6.4 Hz, 2 H) 3.79 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.99 (s, 1 H) 7.17-7.21 (m, 1 H) 7.55 (d, J = 7.8 Hz, 1 H). MS ESI/APCI Dual posi: 316[M +H]⁺, 338[M + Na]⁺. Reference Example A-188

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.11-1.34 (m, 9 H) 2.50 (s, 2 H) 3.76 (s. 2 H) 3.91 (s, 3 H) 4.14 (q, J =7.3 Hz, 2 H) 6.98 (d, J = 7.8Hz, 1 H) 7.06 (s, 1 H) 7.43-7.51 (m, 1 H). MS ESI/APCI Dual posi: 334[M + H]⁺, 356[M + Na]⁺ . MS ESI/APCI Dual nega: 368[M + Cl]⁻. Reference Example A-189

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.06-1.34 (m, 9 H) 2.49 (s, 2 H) 3.78 (s, 2 H) 4.15 (q, J = 7.3 Hz, 2 H) 6.34-6.74 (m, 1 H) 7.29-7.32 (m, 1 H) 7.34 (s, 1 H) 7.59 (d, J = 8.3 Hz, 1 H). MS ESI/APCI Dual posi: 370[M + H]⁺. Reference Example A-190

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17-1.32 (m, 9 H) 2.50 (s, 2 H) 3.70 (s, 2 H) 3.78 (s, 3 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.52-6.75 (m, 3 H). MS ESI/APCI Dual posi: 284[M + H]⁺, 306[M + Na]⁺.

TABLE 18-28 Compound Salt No. Sructure Analytical Data information Reference Example A-191

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.30 (m, 9 H) 2.49 (s, 2 H) 3.65 (s, 2 H) 3.87 (s, 3 H) 4.15 (q, J = 7.3 Hz, 2 H) 6.85-6.92 (m, 1 H) 7.01-7.15 (m, 2 H). MS ESI/APCI Dual posi: 284[M + H]⁺, [M + Na]⁺. Reference Example A-192

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13-1.33 (m, 9 H) 2.49 (s, 2 H) 3.64 (s, 2 H) 3.88 (s, 3 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.87 (d, J = 8.4 Hz, 1 H) 7.17-7.23 (m, 1 H) 7.38 (d, J = 2.2 Hz, 1 H). MS ESI/APCI Dual posi: 300[M + H]⁺, 322[M + Na]⁺. Reference Example A-193

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16-1.32 (m, 9 H) 2.20 (s, 3 H) 2.51 (s, 2 H) 3.62 (s, 2 H) 3.81 (s, 3 H) 4.14 (q, J = 7.3 Hz, 2 H) 6.73-6.79 (m, 1 H) 7.09-7.19 (m, 2 H). MS ESI/APCI Dual posi: 280[M + H]⁺. Reference Example A-194

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.82-1.00 (m, 6 H) 1.27 (t, J = 7.1 Hz, 3 H) 1.87-2.02 (m, 1 H) 2.26-2.44 (m, 1 H) 2.71 (dd, J = 11.8, 4.0 Hz, 1 H) 2.90 (dd, J = 11.8, 10.0 Hz, 1 H) 3.74-3.94 (m, 2 H) 4.11-4.23 (m, 2 H) 7.38-7.47 (m, 2 H) 7.52-7.61 (m, 2 H). MS ESI/APCI Dual posi: 318[M + H]⁺. Reference Example A-195

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.38 (m, 2 H) 0.58-0.69 (m, 2 H) 1.19-1.31 (m, 10 H) 2.50 (s, 2 H) 3.65 (s, 2 H) 3.78 (d, J = 7.1 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.82-6.87 (m, 2 H) 7.22-7.27 (m, 2 H). MS ESI/APCI Dual posi : 306[M + H]⁺. Reference Example A-196

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.26-0.41 (m, 2 H) 0.53-0.68 (m, 2 H) 1.14-1.34 (m, 10 H) 2.23 (s, 3 H) 2.51 (s, 2 H) 3.62 (s, 2 H) 3.79 (d, J = 6.7 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.73 (d, J = 8.1 Hz, 1 H) 7.04-7.13 (m, 2 H) MS ESI/APCI Dual posi: 320[M + H]⁺. Reference Example A-197

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.74-0.87 (m, 2 H) 1.13-1.34 (m, 5 H) 2.74 (s, 2 H) 3.86 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.29-7.37 (m, 1 H) 7.37-7.47 (m, 4 H) 7.52-7.62 (m, 4 H). MS ESI/APCI Dual posi: 310[M + H]⁺, 332[M + Na]⁺ .

TABLE 18-29 Compound Salt No. Structure Analytical Data information Reference Example A-198

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (s, 6 H) 1.26 (t, j = 7.1 Hz, 3 H) 1.99-2.11 (m, 2 H) 2.24-2.44 (m, 2 H) 2.49 (s, 2 H) 3.65 (s, 2 H) 4.06 (t, J = 6.1 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.83-6.92 (m, 1 H) 6.99-7.06 (m, 1 H) 7.12 (dd, J = 12.1, 2.0 Hz, 1 H). MS ESI/APCI Dual posi: 380[M + H]⁺, 402[M + Na]⁺. Reference Example A-199

¹H NMR (300 MHz, CHLOROFORM) δ ppm 1.22 (s, 6 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.34 (s, 3 H) 2.49 (s, 2 H) 3.66 (s, 2 H) 4.14 (q, = 7.1 Hz, 2 H) 7.05-7.23 (m, 2 H) 7.34 (d, J = 1.1 Hz, 1 H). MS ESI/APCI Dual posi: 284[M + H]⁺. 306[M + Na]⁺. Reference Example A-200

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.58-0.73 (m, 2 H) 0.86-1.00 (m, 2 H) 1.18-1.29 (m, 9 H) 1.81-1.97 (m, 1 H) 2.50 (s, 2 H) 3.66 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.95-7.10 (m, 2 H) 7.19-7.25 (m, 2 H). MS ESI/APCI Dual posi: 276[M + H]⁺. Reference Example A-201

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.28-0.40 (m, 2 H) 0.55-0.71 (m, 2 H) 1.13-1.34 (m, 10 H) 2.49 (s, 2 H) 3.64 (s, 2 H) 3.85 (d, J = 7.0 Hz, 2 H) 4.14 (q, j = 7.1 Hz, 2 H) 6.82-6.92 (m, 1 H) 6.95-7.05 (m, 1 H) 7.06-7.15 (m, 1 H). MS ESI/APCI Dual posi: 324[M + H]⁺. Reference Example A-202

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.0 Hz, 3 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.90 (t, J = 6.5 Hz, 2 H) 3.77 (s, 2 H) 4.14 (q, J = 7.0 Hz, 2 H) 6.85-7.09 (m, 6 H) 7.21-7.35 (m, 2 H). MS ESI/APCI Dual posi: 318[M + H]⁺, 340[M + Na]⁺. MS ESI/APCI Dual nega: 316[M − H]⁻. Reference Example A-203

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.34 (m, 9 H) 2.35 (s, 3 H) 2.49 (s, 2 H) 3.66 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.83 (d, J = 8.4 Hz, 1 H) 7.00 (d, J = 8.3 Hz, 2 H) 7.18 (d, J = 8.3 Hz, 2 H) 7.71 (dd, J = 8.4, 2.4 Hz, 1 H) 8.12 (d, J = 2.4 Hz, 1 H). MS ESI/APCI Dual posi: 343[M + H]⁺, 365[M + Na]⁺. MS ESI/APCI Dual nega: 341[M − H]⁻. Reference Example A-204

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.73-0.79 (m, 2 H) 1.19-1.29 (m, 5 H) 2.67 (s, 2 H) 3.76 (s, 2 H) 4.12 (q, J = 7.1 Hz, 2 H) 7.17-7.24 (m, 2 H) 7.38-7.50 (m, 2 H). MS ESI/APCI Dual posi: 312[M + H]⁺.

TABLE 18-30 Compound Salt No. Structure Analytical Data information Reference Example A-205

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.71-0.82 (m, 2 H) 1.16-1.32 (m, 5 H) 2.70 (s, 2 H) 3.81 (s, 2 H) 4.12 (q, J = 7.1 Hz, 2 H) 7.07-7.23 (m, 2 H) 7.31-7.43 (m, 2H). MS ESI/APCI Dual posi: 318[M + H]⁺. Reference Example A-206

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.33 (s, 3 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.90 (t, J = 6.5 Hz, 2 H) 3.77 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.87-6.96 (m, 4 H) 7.09-7.16 (m, 2 H) 7.22-7.29 (m, 2 H). MS ESI/APCI Dual posi: 314[M + H]⁺, 336[M + Na]⁺. MS ESI/APCI Dual nega: 312[M − H]⁻. Reference Example A-207

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14-1.35 (m, 9 H) 1.75-1.90 (m, 1 H) 1.90-2.22 (m, 3 H) 2.25-2.38 (m, 2 H) 2.51 (s, 2 H) 3.43-3.60 (m, 1 H) 3.68 (s, 2 H) 4.14 (q, J = 7.0 Hz, 2 H) 7.13-7.19 (m, 2 H) 7.24-7.30 (m, 2 H). MS ESI/APCI Dual posi: 290[M + H]⁺, 312[M + Na]⁺. Reference Example A-208

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.65-0.82 (m, 2 H) 0.94-1.06 (m, 2 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.11- 2.27 (m, 1 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.88 (t, J = 6.4 Hz, 2 H) 3.79 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.99 (d, J = 7.9 Hz, 1 H) 7.35-7.42 (m, 1 H) 7.52-7.58 (m, 1 H). MS ESI posi: 316[M + H]⁺. Reference Example A-209

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.58-0.73 (m, 2 H) 0.73-0.83 (m, 2 H) 0.87-0.99 (m, 2 H) 1.15-1.31 (m, 5 H) 1.75-1.93 (m, 1 H) 2.69 (s, 2 H) 3.77 (s, 2 H) 4.11 (q, J = 7.1 Hz, 2 H) 6.96-7.06 (m, 2 H) 7.18-7.25 (m, 2 H). MS ESI/APCI Dual posi: 274[M + H]⁺. Reference Example A-210

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.70-0.82 (m, 2 H) 1.17-1.31 (m, 5 H) 2.68 (s, 2 H) 3.78 (s, 2 H) 4.12 (q, J = 7.1 Hz, 2 H) 7.22-7.34 (m, 4 H). MS ESI/APCI Dual posi: 268[M + H]⁺. Reference Example A-211

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13-1.34 (m, 9 H) 2.49 (s, 2 H) 3,86 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2H) 6.57 (s, 1 H) 7.37-7.48 (m, 2 H) 7.65-7.76 (m, 2 H). MS ESI posi: 337[M + H]⁺, 359[M + Na]⁺.

TABLE 18-31 Compound Salt No. Structure Analytical Data information Reference Example A-212

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (s, 6 H) 1.27 (t, J = 7.1 Hz, 3 H) 2.09-2.23 (m, 2 H) 2.23-2.52 (m, 5 H) 2.76 (d, J = 7.3 Hz, 2 H) 3.45-3.71 (m, 1 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.13-7.21 (m, 1 H) 7.22-7.36 (m, 4 H). MS ESI posi: 290[M + H]⁺. Reference Example A-213

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15 (s, 6 H) 1.25 (t, J = 7.1 Hz, 3 H) 1.69-1.85 (m, 2 H) 2.29-2.65 (m, 7 H) 3.28-3.51 (m, 1 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.13-7.23 (m, 3 H) 7.26-7.33 (m, 2 H). MS ESI posi: 290[M + H]⁺. Reference Example A-214

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.91-1.10 (m, 2 H) 1.27 (t, J = 7.1 Hz, 3 H) 1.32-1.79 (m, 6 H) 1.82-1.99 (m, 1 H) 2.44-2.61 (m, 4 H) 2.64-2.74 (m, 1 H) 2.82-2.90 (m, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 6.99-7.35 (m, 5 H). MS ESI/APCI Dual posi: 290[M + H]⁺. Reference Example A-215

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14-1.33 (m, 9 H) 2.50 (s, 2 H) 3.67 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.27-4.38 (m, 2 H) 6.86-6.91 (m, 2 H) 7.28-7.33 (m, 2 H). MS ESI/APCI Dual posi: 334[M + H]⁺. Reference Example A-216

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.87 (t, J = 6.4 Hz, 2 H) 3.74 (s, 2 H) 4.15 (q, j = 7.1 Hz, 2 H) 4.39 (q, J = 8.1 Hz, 2 H) 6.93 (d, J = 8.4 Hz, 1 H) 7.19 (dd, J = 8.4, 2.2 Hz, 1 H) 7.39 (d, J = 2.2 Hz, 1 H). MS ESI/APCI Dual posi: 340[M + H]⁺. Reference Example A-217

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.44-0.62 (m, 2 H) 0.71-0.83 (m, 2 H) 1.28 (t, J = 7.1 Hz, 3 H) 2.52 (s, 2 H) 3.86 (s, 2 H) 4.18 (q, J = 7.1 Hz, 2 H) 7.29-7.47 (m, 5 H) 7.49-7.61 (m, 4 H). MS ESI/APCI Dual posi: 310[M + H]⁺, 332[M + Na]⁺. MS ESI/APCI Dual nega: 344[M + Cl]⁻. Reference Example A-218

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.45-0.57 (m, 2 H) 0.68-0.82 (m, 2 H) 1.27 (t, J = 7.1 Hz, 3 H) 2.49 (s, 2 H) 3.88 (s, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 7.34-7.49 (m, 2 H) 7.48-7.61 (m, 2 H). MS ESI/APCI Dual posi: 302[M + H]⁺, 324[M + Na]⁺. MS ESI/APCI Dual nega: 300[M − H]⁻.

TABLE 18-32 Compound Salt No. Structure Analytical Data information Reference Example A-219

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.31 (m, 3 H) 2.47-2.57 (m, 2 H) 2.89 (t, J = 6.3 Hz, 2 H) 3.79 (s, 2 H) 4.08-4.19 (m, 2 H) 6.98 (d, J = 8.4 Hz, 1 H) 7.16-7.25 (m, 2 H) 7.63-7.71 (m, 2 H) 7.78 (dd, J = 8.4, 2.5 Hz, 1 H) 8.13 (dd, J = 2.5, 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 326[M + H]⁺, 348[M + Na]⁺. MS ESI/APCI Dual nega: 324[M −H]⁻. Reference Example A-220

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.93 (t, J = 6.5 Hz, 2 H) 3.83 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.03 (t, J = 4.8 Hz, 1 H) 7.10-7.19 (m, 2 H) 7.34-7.43 (m, 2 H) 8.51-8.59 (m, 2 H). MS ESI/APCI Dual posi: 302[M + H]⁺, 324[M + Na]⁺. Reference Example A-221

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.99-1.07 (m, 3 H) 1.20-1.29 (m, 9 H) 1.74-1.86 (m, 2 H) 2.50 (s, 2 H) 3.65 (s, 2 H) 3.86-3.96 (m, 2 H) 4.10-4.19 (m, 2 H) 6.79-6.87 (m, 2 H) 7.22-7.28 (m, 2 H). MS ESI posi: 294[M + H]⁺. Reference Example A-222

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.36 (m, 15 H) 2.50 (s, 2 H) 3.64 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.46-4.58 (m, 1 H) 6.79-6.86 (m, 2 H) 7.20-7.28 (m, 2 H). MS ESI posi: 294[M + H]⁺. Reference Example A-223

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.80-0.97 (m, 2 H) 1.13-1.19 (m, 6 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.30-1.41 (m, 1 H) 1.74 (dt, J = 8.9, 4.7 Hz, 1 H) 2.42 (s, 2 H) 2.47 (dd, J = 11.0, 7.1 Hz, 1 H) 2.70 (dd, J = 11.0, 6.4 Hz, 1 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.02-7.08 (m, 2 H) 7.09-7.16 (m, 1 H) 7.20-7.28 (m, 2 H). MS ESI posi: 276[M + H]⁺. Reference Example A-224

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.39 (d, J = 6.7 Hz, 3 H) 2.41-2.54 (m, 2 H) 2.64-2.86 (m, 2 H) 3.74-3.92 (m, 1 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.29-7.48 (m, 5 H) 7.50-7.67 (m, 4 H). Reference Example A-225

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.93 (s, 9 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.90 (t, J = 6.5 Hz, 2 H) 3.10 (s, 2 H) 3.80 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.50 (s, 2 H) 7.28-7.30 (m, 4 H). MS ESI/APCI Dual posi: 308[M + H]⁺, 330[M + Na]⁺.

TABLE 18-33 Compound Salt No. Structure Analytical Data information Reference Example A-226

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.35 (m, 2 H) 0.36-0.42 (m, 2 H) 1.15 (s, 3 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.24 (s, 2 H) 3.79 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.51 (s, 2 H) 7.28-7.31 (m, 4 H). MS ESI/APCI Dual posi: 306[M + H]⁺, 328[M + Na]⁺. Reference Example A-227

¹H NMR(300 MHz, CHLOROFORM-d) δ ppm 1.21-1.29 (m, 9 H) 1.40 (t, J = 7.0 Hz, 3 H) 2.50 (s, 2 H) 3.65 (s, 2 H) 4.01 (q, J = 7.0 Hz, 2 H) 4.14 (q, J = 7.0 Hz, 2 H) 6.81-6.86 (m, 2 H) 7.21-7.27 (m, 2 H). MS ESI/APCI Dual posi: 280[M + H]⁺. Reference Example A-228

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.25-0.41 (m, 2 H) 0.54-0.69 (m, 2 H) 1.15-1.35 (m, 4 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.73 (s, 2 H) 3.78 (d, J = 7.0 Hz, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 6.82-6.89 (m, 2 H) 7.18-7.24 (m, 2 H). MS ESI/APCI Dual posi: 278[M + H]⁺. Reference Example A-229

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.60-0.75 (m, 2 H) 0.88-1.01 (m, 2 H) 1.72-1.95 (m, 3 H) 1.95-2.17 (m, 4 H) 2.72 (s, 2 H) 3.64 (s, 2 H) 3.68 (s, 3 H) 6.99-7.04 (m, 2 H) 7.19-7.24 (m, 2 H). MS ESI/APCI Dual posi: 274[M +H]⁺, 296[M + Na]⁺. Reference Example A-230

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.63-0.71 (m, 2 H) 0.90-0.98 (m, 2 H) 1.25 (t, J = 7.1 Hz, 3 H) 1.82-1.99 (m, 5 H) 2.32-2.48 (m, 2 H) 2.89 (s, 2 H) 3.75 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.95-7.07 (m, 2 H) 7.13-7.24 (m, 2 H). MS ESI/APCI Dual posi.: 288[M + H]⁺, 310[M + Na]⁺. Reference Example A-231

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1 78-2.03 (m, 4 H) 2.05-2.21 (m, 2 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.68-2.82 (m, 1 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.73 (s, 2 H) 3.91 (d, J = 6.7 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.82-6.89 (m, 2 H) 7.17-7.25 (m, 2 H). MS ESI/APCI Dual posi: 292[M + H]⁺. Reference Example A-232

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13-1.36 (m, 9 H) 1.80-2.03 (m, 4 H) 2.03-2.22 (m, 2 H) 2.50 (s, 2 H) 2.70-2.88 (m, 1 H) 3.65 (s, 2 H) 3.90 (d, J = 6.7 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.80-6.88 (m, 2 H) 7.19-7.30 (m, 2 H). MS ESI/APCI Dual posi: 320[M + H]⁺.

TABLE 18-34 Compound Salt No. Structure Analytical Data information Reference Example A-233

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.06 (s, 2 H) 6.93 (d, J = 8.7 Hz, 2 H) 7.20-7.25 (m, 3 H) 7.30-7.46 (m, 4 H). MS ESI/APCI Dual posi: 314[M + H]⁺, 336[M + Na]⁺. MS ESI/APCI Dual nega: 312[M − H]⁻. Reference Example A-234

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.01 (s, 2 H) 6.88-6.94 (m, 2 H) 7.02-7.11 (m, 2 H) 7.21-7.26 (m, 2 H) 7.36-7.43 (m, 2 H). MS ESI/APCI Dual posi: 332[M + H]⁺, 354[M + Na]⁺. MS ESI/APCI Dual nega: 330[M − H]⁻. Reference Example A-235

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.02 (s, 2 H) 6.87-6.94 (m, 2 H) 7.20-7.26 (m, 2 H) 7.35 (s, 4 H). MS ESI/APCI Dual posi: 348[M + H]⁺, 370[M + Na]⁺. MS ESI/APCI Dual nega: 346[M − H]⁻, 382[M + Cl]⁻. Reference Example A-236

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.76-1.92 (m, 1H) 1.95-2.10 (m, 1 H) 2.10-2.27 (m, 2 H) 2.27-2.43 (m, 2 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.69-4.00 (m, 3 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.41-7.63 (m, 3 H). MS ESI/APCI Dual posi: 330[M + H]⁺. Reference Example A-237

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.83 (q, J = 5.5 Hz, 1 H) 0.91 (s, 3 H) 0.93 (s, 3 H) 1.02 (td, J = 8.4, 5.5 Hz, 1 H) 1.24 (t, J = 7.1 Hz, 3 H) 1.27-1.41 (m, 1 H) 2.06 (d, J = 14.0 Hz, 1 H) 2.14-2.28 (m, 3 H) 2.32 (dd, J = 11.2, 6.8 Hz, 1 H) 4.08 (q, J = 7.1 Hz, 2 H) 7.07-7.39 (m, 5 H). MS ESI/APCI Dual posi: 276[M + H]⁺. Reference Example A-238

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.81-1.93 (m, 1 H) 1.95-2.12 (m, 1 H) 2.13-2.26 (m, 2 H) 2.26-2.41 (m, 2 H) 2.55 (t, J = 6.4 Hz, 2 H) 2.91 (t, J = 6.4 Hz, 2 H) 3.77-3.98 (m, 3 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.14-7.28 (m, 1 H) 7.48-7.60 (m, 2 H). MS ESI/APCI Dual posi : 330[M + H]⁺. Reference Example A-239

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.05-0.21 (m, 2 H) 0.37-0.58 (m, 2 H) 0.74-0.95 (m, 1 H) 1.25 (t, J = 7.1 Hz, 3 H) 1.67 (q, J = 6.7 Hz, 2 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.73 (s, 2 H) 4.02 (t, J = 6.8 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.81-6.90 (m, 2 H) 7.18-7.25 (m, 2 H). MS ESI/APCI Dual posi: 292[M + H]⁺.

TABLE 18-35 Compound Salt No. Structure Analytical Data information Reference Example A-240

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.05-0.20 (m, 2 H) 0.40-0.54 (m, 2 H) 0.75-0.92 (m, 1 H) 1.14-1.34 (m, 9 H) 1.64-1.72 (m, 2 H) 2.51 (s, 2 H) 3.65 (s, 2 H) 4.03 (q, J = 6.8 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.82-6.88 (m, 2 H) 7.22-7.28 (m, 2 H). MS ESI/APCI Dual posi: 320[M + H]⁺. Reference Example A-241

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.02-1.86 (m, 8 H) 2.43-2.57 (m, 4 H) 2.60-2.94 (m, 6 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.12 (s, 2 H) 7.20-7.46 (m, 5 H). MS ESI/APCI Dual posi: 349[M + H]⁺. Reference Example A-242

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm −0.11-0.10 (m, 2 H) 0.34-0.48 (m, 2 H) 0.59-0.79 (m, 1 H) 1.25 (t, J = 7.1 Hz, 3 H) 1.44-1.54 (m, 2 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.64-2.73 (m, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.77 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.11-7.18 (m, 2 H) 7.18-7.25 (m, 2 H). MS ESI/APCI Dual posi: 276[M + H]⁺, 298[M + Na]⁺. Reference Example A-243

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.25-0.41 (m, 2 H) 0.58-0.69 (m, 2 H) 1.25 (t, J = 7.1 Hz, 3 H) 1.83-1.99 (m, 5 H) 2.31-2.47 (m, 2 H) 2.88 (s, 2 H) 3.73 (s, 2 H) 3.79 (d, J = 6.8 Hz, 2 H; 4.15 (q, J = 7.1 Hz, 2 H) 6.82-6.88 (m, 2 H) 7.18-7.24 (m, 2 H). MS ESI/APCI Dual posi: 318[M + H]⁺. Reference Example A-244

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.37 (m, 2H) 0.47-0.53 (m, 2 H) 0.59-0.68 (m. 2 H) 0.69-0.76 (m, 2 H) 1.24-1.31 (m, 4 H) 2.49 (s, 2 H) 3.74 (s, 2 H) 3.77 (d, J = 7.0 Hz, 2 H) 4.17 (q, J= 7.1 Hz, 2 H) 6.80-6.87 (m, 2 H) 7.16-7.23 (m, 2 H). MS ESI/APCI Dual posi: 304[M + H]⁺. Reference Example A-245

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.31 (m, 3 H) 2.43-2.58 (m, 2 H) 2.82-2.92 (m, 2 H) 3.75 (s, 2 H) 4.07- 4.19 (m, 2 H) 6.87 (d, J = 8.4 Hz, 1 H) 7.01-7.15 (m, 4 H) 7.65-7.72 (m, 1 H) 8.04-8.10 (m, 1 H). MS ESI/APCI Dual posi: 319[M + H]⁺, 341[M + Na]⁺. MS ESI/APCI Dual nega: 317[M − H]⁻. Reference Example A-246

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21-1.30 (m, 3 H) 2.47-2.57 (m, 2 H) 2.82-2.92 (m, 2 H) 3.76 (s, 2 H) 4.07- 4.20 (m, 2 H) 6.89 (dd, J = 8.4, 0.8 Hz, 1 H) 7.01-7.10 (m, 2 H) 7.29-7.38 (m, 2 H) 7.71 (dd, J = 8.5, 2.4 Hz, 1 H) 8.09 (dd, J = 2.4, 0.8 Hz, 1 H). MS ESI/APCI Dual posi: 335[M + H]⁺, 357[M + Na]⁺. MS ESI/APCI Dual nega: 333 [M − H]⁻.

TABLE 18-36 Compound Salt No. Structure Analytical Data information Reference Example A-247

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.19-1.29 (m, 3 H) 2.48-2.58 (m, 2 H) 2.85-2.94 (m, 2 H) 3.78 (s, 2 H) 4.07-4.22 (m, 2 H) 6.95 (d, J = 8.4 Hz, 1 H) 7.19-7.29 (m, 2 H) 7.58-7.69 (m, 2 H) 7.76 (dd, J = 8.4, 2.5 Hz, 1 H) 8.12 (d, J = 2.5 Hz, 1 H). MS ESI/APCI Dual posi: 369[M + H]⁺, 381[M + Na]⁺. Reference Example A-248

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.20-1.29 (m, 3 H) 2.36 (s, 3 H) 2.49-2.57 (m, 2 H) 2.89 (t, J = 6.4 Hz, 2 H) 3.76 (s, 2 H) 4.08-4.19 (m, 2 H) 6.80-8.85 (m, 3 H) 6.97-7.05 (m, 1 H) 7.20-7.33 (m, 1 H) 7.68 (dd, J = 8.5. 2.5 Hz, 1 H) 8.12 (dd, J = 2.5, 0.6 Hz, 1 H). MS ESI/APCI Dual posi : 315[M + H]⁺, 337[M + Na]⁺. MS ESI/APCI Dual nega: 313[M − H]⁻. Reference Example A-249

¹H NMR (300 MHz. CHLOROFORM-d) δ ppm 1.18-1.32 (m, 3 H) 2.46-2.57 (m, 2 H) 2.83-2.93 (m, 2 H) 3.77 (s, 2 H) 4.07-4.18 (m, 2 H) 6.79-7.01 (m, 4 H) 7.28-7.40 (m, 1 H) 7.67-7.75 (m, 1 H) 8.13 (dd, J = 2.5, 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 318[M + H]⁺, 341[M + Na]⁺. MS ESI/APCI Dual nega: 317[M − H]⁻. Reference Example A-250

¹H NMR (300 MHz. CHLOROFORM-d) δ ppm 1.21-1.31 (m, 3 H) 2.32 (s, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 3.78 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.73-6.84 (m, 2 H) 6.86-7.00 (m, 3 H) 7.20 (t, J = 7.9 Hz, 1 H) 7.23-7.31 (m, 2 H). MS ESI/APCI Dual posi: 314[M + H]⁺, 336 [M + Na]⁺. MS ESI/APCI Dual nega: 312[M −H]⁻. Reference Example A-251

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 3.79 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.62-6.72 (m, 1 H) 6.73-6.82 (m, 2 H) 6.93-7.05 (m, 2 H) 7.16-7.36 (m, 3 H). MS ESI/APCI Dual posi: 318[M + H]⁺, 340[M + Na]⁺. MS ESI/APCI Dual nega: 316[M − H]⁻. r Reference Example A-252

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.31 (m, 3H) 2.55 (t, J = 6.5 Hz, 2 H) 2.94 (t, J = 6.5 Hz, 2 H) 3.91 (s, 2 H) 4.07-4.22 (m, 2 H) 6.87-7.11 (m, 4 H) 7.17-7.33 (m, 2 H) 8.32 (d, J = 2.8 Hz, 1H). MS ESI/APCI Dual posi: 319[M + H]⁺, 341[M + Na]⁺. MS ESI/APCI Dual nega: 317[M − H]⁻. Reference Example A-253

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.33 (m, 3 H) 2.34 (s, 3 H) 2.46-2.62 (m, 2 H) 2.94 (t, J = 6.6 Hz, 2 H) 3.90 (s, 2 H) 4.06-4.21 (m, 2 H) 6.79-7.00 (m, 2 H) 7.10-7.18 (m, 2 H) 7.19-7.30 (m, 2 H) 8.32 (dd, J = 2.6, 0.9 Hz, 1 H). MS ESI/APCI Dual posi: 315[M + H]⁺, 337[M + Na]⁺. MS ESI/APCI Dual nega: 313[M − H]⁻.

TABLE 18-37 Compound Salt No. Structure Analytical Data information Reference Example A-254

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.50 (t, J = 6.4 Hz, 2 H) 2.86 (t, J = 6.4 Hz, 2 H) 3.75 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 6.94 (d, J = 8.1 Hz, 1 H) 7.31-7.44 (m, 2 H) 7.44-7.59 (m, 3 H) 8.37 (d, J = 1.7 Hz, 1 H). MS ESI/APCI Dual posi: 351[M + H]⁺. Reference Example A-255

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.61-1.77 (m, 1 H) 1.78-1.93 (m, 1 H) 2.07-2.24 (m, 2 H) 2.37-2.49 (m, 2 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.72 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 4.52-4.72 (m, 1 H) 6.69-6.83 (m, 2 H) 7.16-7.23 (m, 2 H). MS ESI/APCI Dual posi: 278[M + H]⁺, 300[M + Na]⁺. Reference Example A-256

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.03 (s, 3H) 2.07 (s, 3 H) 2.56 (t, J = 6.5 Hz, 2 H) 2.95 (t, J = 6.5 Hz, 2 H) 3.70 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.13-7.41 (m, 4 H) 7.58 (s, 1H). MS ESI/APCI Dual posi: 302[M + H]⁺, 324[M + Na]⁺. MS ESI/APCI Dual nega: 300[M − H]⁻, 336[M + Cl]⁻. Reference Example A-257

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.70-0.82 (m, 4 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.64-3.78 (m, 3 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.97-7.03 (m, 2 H) 7.20-7.25 (m, 2 H). MS ESI/APCI Dual posi: 264[M + H]⁺, 286[M + Na]⁺. MS ESI/APCI Dual nega: 262[M − H]⁻. I Reference Example A-258

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.33 (m, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 3.78 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.83-7.02 (m, 4 H) 7.20-7.35 (m, 4 H). [MS ESI/APCI Dual posi: 334[M + H]⁺, 356[M + Na]⁺. MS ESI/APCI Dual nega: 332[M − H]⁻. Reference Example A-259

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.44-0.55 (m, 2 H) 0.30-0.69 (m, 2 H) 0.69-0.77 (m, 2 H) 0.86-0.99 (m, 2 H) 1.27 (t, J = 7.1 Hz, 3 H) 1.86 (tt, J = 8.5, 5.1 Hz, 1 H) 2.49 (s, 2 H) 3.76 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 6.95-7.05 (m, 2 H) 7.12-7.22 (m, 2 H). MS ESI/APCI Dual posi: 274[M + H]⁺. Reference Example A-260

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.39 (m, 2 H) 0.57-0.69 (m, 2 H) 1.17-1.34 (m, 1 H) 1.71-1.94 (m, 2 H) 1.95-2.16 (m, 4 H) 2.72 (s, 2 H) 3.62 (s, 2 H) 3.68 (s, 3 H) 3.75-3.80 (m, 2 H) 6.81-6.87 (m, 2 H) 7.21-7.26 (m, 2 H). MS ESI/APCI Dual posi: 304[M + H]⁺.

TABLE 18-38 Compound Salt No. Structure Analytical Data information Reference Example A-261

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.31 (s. 3 H) 2.56 (t, J = 6.5 Hz, 2 H) 2.95 (t, J = 6.5 Hz, 2 H) 3.70 (s, 2 H) 4.15 (d, J = 7.1 Hz, 2 H) 7.32-7.52 (m, 5 H) 7.59 (s, 1 H). MS-ESI/APCI Dual posi: 283[M + H]⁺, 310[M + Na]⁺. Reference Example A-262

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3H) 2.06 (quin, J = 7.4 Hz, 2 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.81-2.96 (m, 6 H) 3.76 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.04-7.10 (m, 1 H) 7.14-7.20 (m, 2 H). MS ESI/APC1 Dual posi: 248[M + H]⁺, 270[M + Na]⁺. Reference Example A-263

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.93 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.28-7.35 (m, 2 H) 7.43 (dd, J = 5.4, 0.5 Hz, 1 H) 7.75-7.79 (m, 1 H) 7.83 (d, J = 8.4 Hz, 1 H). MS ESI/APCI Dual posi: 264[M + H]⁺, 286[M + Na]⁺. Reference Example A-264

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.49-1.71 (m, 2 H) 1.71-1.99 (m, 6 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.72 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 4.66-4.80 (m, 1 H) 6.74-6.89 (m, 2 H) 7.14-7.24 (m, 2 H). MS ESI/APCI Dual posi: 292[M + H]⁺. Reference Example A-265

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07-1.37 (m, 9 H) 1.51-1.94 (m, 8 H) 2.50 (s, 2 H) 3.64 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.68-4.80 (m, 1 H) 6.77-6.84 (m, 2 H) 7.19-7.26 (m, 2 H). MS ESI/APCI Dual posi: 320[M + H]⁺. Reference Example A-266

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.19-1.31 (m, 3 H) 2.45-2.58 (m, 5 H) 2.83-2.95 (m, 2 H) 3.78 (s, 2 H) 4.06-4.22 (m, 2 H) 6.90-6.98 (m, 2 H) 7.07-7.13 (m, 1 H) 7.16-7.23 (m, 1 H) 7.27-7.34 (m, 2 H) 8.29 (d, J = 2.8 Hz,1 H). MS ESI/APCI Dual posi: 315[M + H]⁺. Reference Example A-267

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.44-2.56 (m, 2 H) 2.81-2.91 (m, 2 H) 3.75 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.91-6.97 (m, 1 H) 7.10-7.25 (m, 4 H) 7.67-7.75 (m, 1 H) 8.05 (dd, J = 2.5, 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 319[M + H]⁺, 341[M + Na]⁺.

TABLE 18-39 Compound Salt No. Structure Analytical Data information Reference Example A-268

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.33 (m, 3 H) 2.18 (s, 3 H) 2.44-2.56 (m, 2 H) 2.82-2.93 (m, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.81 (dd, J = 8.5, 0.7 Hz, 1 H) 6.98-7.07 (m, 1 H) 7.08-7.30 (m, 3 H) 7.67 (dd, J = 8.5, 2.5 Hz. 1 H) 8.08 (dd, J = 2.5, 0.7 Hz, 1 H). MS ESI/APCI Dual pos: 315[M + H]⁺, 337[M + Na]⁺. Reference Example A-269

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17 (s, 6 H) 1.23 (t, J = 7.1 Hz, 3 H) 2.35 (s, 3 H) 2.63 (s, 2 H) 3.72 (s, 2 H) 4.11 (q, J = 7.1 Hz, 2 H) 6.84 (d, J = 8.5 Hz, 1 H) 6.96-7.08 (m, 2 H) 7.12-7.23 (m, 2 H) 7.66 (dd, J = 8.5, 2.4 Hz, 1 H) 8.08 (d, J = 2.4 Hz, 1 H). MS ESI/APCI Dual posi: 343[M + H]⁺. Reference Example A-270

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.68-0.84 (m, 2 H) 1.11-1.34 (m, 5 H) 2.35 (s, 3 H) 2.69 (s, 2 H) 3.75 (s, 2 H) 4.11 (q, J = 6.9 Hz, 2 H) 6.85 (d, J = 8.4 Hz, 1 H) 6.97-7.05 (m, 2 H) 7.15-7.22 (m, 2 H) 7.69 (dd, J = 8.4, 2.4 Hz, 1 H), 8.09 (d, J = 2.4 Hz. 1 H). MS ESI/APCI Dual posi: 341[M + H]⁺. ' Reference Example A-271

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.79-2.00 (m, 4 H) 2.25-2.51 (m, 5 H) 2.88 (s, 2 H) 3.74 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.84 (d, J = 8.4 Hz, 1 H) 6.98-7.05 (m, 2 H) 7.15-7.22 (m, 2 H) 7.66 (dd, J = 8.4, 2.5 Hz, 1 H) 8.08 (d, J = 2.5 Hz, 1 H). MS ESI/APCI Dual posi: 355[M + H]⁺. Reference Example A-272

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.30-0.39 (m, 2 H) 0.58-0.69 (m, 2 H) 0.84-0.92 (m, 2 H) 1.22 (t, J = 7.1 Hz, 3 H) 1.25-1.34 (m, 3 H) 2.78 (s, 2 H) 3.79 (d, J = 7.0 Hz, 2 H) 3.84 (s, 2 H) 4.11 (q, J = 7.1 Hz, 2 H) 6.83-6.91 (m, 2 H) 7.22-7.29 (m, 2 H). MS ESI/APCI Dual posi: 304[M + H]⁺. Reference Example A-273

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.72-1.95 (m, 2 H) 1.96-2.16 (m, 4 H) 2.34 (s, 3 H) H) 3.68 (s, 3H) 6.84 (d, J = 8.5 Hz, 1 H) 6.97-7.04 (m, 2 H) 7.14-7.21 (m, 2 H) 7.69 (dd, J = 8.5, 2.5 Hz, 1 H) 8.11 (d, J = 2.5 Hz, 1 H). MS ESI/APCI Dual posi: 341[M + H]⁺. Reference Example A-274

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07-1.37 (m, 9 H) 2.53 (s, 2 H) 3.87-4.04 (m, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.15 (s, 1 H) 7.38-7.47 (m, 3 H) 7.90-7.97 (m, 2 H). MS ESI/APCI Dual posi: 319[M + H]⁺, 341[M + Na]⁺.

TABLE 18-40 Compound Salt No. Structure Analytical Data information Reference Example A-275

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15-1.32 (m, 3 H) 2.46-2.58 (m, 2 H) 2.83-2.94 (m, 2 H) 3.77 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.89-6.97 (m, 2 H) 6.98-7.22 (m, 4 H) 7.27-7.30 (m, 2 H). MS ESI/APCI Dual posi: 318[M + H]⁺, 340[M + Na]⁺. MS ESI/APCI Dual nega: 316[M − H]⁻. Reference Example A-276

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.24 (s, 3 H) 2.47-2.57 (m, 2 H) 2.86-2.93 (m, 2 H) 3.76 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.79-6.92 (m, 3 H) 7.01-7.09 (m, 1 H) 7.11-7.19 (m, 1 H) 7.21-7.28 (m, 3 H). MS ESI/APCI Dual posi: 314[M + H]⁺, 336[M + Na]⁺. MS ESI/APCI Dual nega: 312[M − H]⁻. Reference Example A-277

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.31 (m, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.83-2.93 (m, 2 H) 3.77 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.90 (d, J = 8.4 Hz, 1 H) 6.98-7.07 (m, 1 H) 7.10-7.21 (m, 2 H) 7.27-7.35 (m, 1 H) 7.67-7.75 (m, 1 H) 8.12 (dd, J = 2.5, 0.6 Hz, 1 H) MS ESI/APCI Dual posi: 335[M + H]⁺, 357[M + Na]⁺. Reference Example A-278

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.30 (m, 3 H) 2.47-2.57 (m, 2 H) 2.84-2.93 (m, 2 H) 3.78 (s, 2 H) 4.15 (q, J = 7.0 Hz, 2 H) 6.88-6.97 (m, 1 H) 7.28-7.36 (m, 1 H) 7.37-7.56 (m, 3 H) 7.75 (dd, J = 8.4. 2.5 Hz, 1 H) 8.11 (dd, J = 2.5, 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 369[M + H]⁺, 391[M + Na]⁺. Reference Example A-279

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3H) 2.47-2.58 (m, 2 H) 2.85-2.96 (m, 2 H) 3.74-3.80 (m, 5 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.52-6.60 (m, 2 H) 6.64 (ddd, J = 8.3, 2.4, 1.0 Hz, 1 H) 6.93-7.03 (m, 2 H) 7.16-7.32 (m, 3 H). MS ESI/APCI Dual posi: 330[M + H]⁺, 352[M + Na]⁺, MS ESI/APCI Dual nega: 328[M − H]⁻. Reference Example A-280

¹H NMR (300 MHz, CHLOROFORH-d) δ ppm 1.20-1.31 (m, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.84-2.93 (m, 2 H) 3.77 (s, 2 H) 4.08-4.25 (m, 2 H) 6.86-6.95 (m, 1 H) 7.00-7.12 (m, 3 H) 7.33-7.44 (m, 1 H) 7.74 (dd J = 8.4, 2.3 Hz, 1 H) 8.06-8.08 (m, 1 H). MS ESI/APCI Dual posi: 385[M + H]⁺, 407[M + Na]⁺. Reference Example A-281

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.31 (m, 3 H) 2.46-2.58 (m, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.81 (s, 2 H) 4.05-4.24 (m, 2 H) 6.79-6.93 (m, 1 H) 7.01-7.12 (m, 2 H) 7.30-7.48 (m, 3 H) 8.02 (d, J = 3.1 Hz, 1 H). MS ESI/APCI Dual posi: 319[M + H]⁺, 341 [M + Na]⁺.

TABLE 18-41 Compound Salt No. Structure Analytical Data information Reference Example A-282

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.81 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.73-6.92 (m, 1 H) 7.00-7.13 (m, 2 H) 7.31-7.42 (m, 2 H) 7.56-7.70 (m, 1 H) 8.12 (dd, J = 2.6, 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 335[M + H]⁺, 357[M + Na]⁺. MS ESI/APCI Dual nega: 333[M − H]⁻. Reference Example A-283

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10-1.32 (m, 3 H) 2.40-2.61 (m, 2 H) 2.77-2.96 (m, 2 H) 3.84 (s, 2 H) 4.02-4.21 (m, 2 H) 6.81 (dd, J = 8.1, 1.2 Hz, 1 H) 6.83-7.14 (m, 5 H) 7.16-7.24 (m, 1 H) 7.40 (dd, J = 7.5, 1.9 Hz, 1 H). MS ESI/APCI Dual posi: 318[M + H]⁺, 340[M + Na]⁺. Reference Example A-284

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.3 Hz, 2 H) 2.88 (t, J = 6.3 Hz, 2 H) 3.76 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.34 (q, J = 8.1 Hz, 2 H) 6.80-6.95 (m, 2 H) 7.17-7.35 (m, 2 H). MS ESI/APCI Dual posi: 306[K + H]⁺. Reference Example A-285

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.87 (t, J = 6,4 Hz, 2 H) 3.75 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.40 (q, J = 8.2 Hz. 2 H) 6.94-7.05 (m, 2 H) 7.13 (dd, J = 11.8, 1.7 Hz, 1 H). MS ESI/APCI Dual posi: 324[M + H]⁺. Reference Example A-286

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21-1.35 (m, 9 H) 2.54 (s, 2H) 3.84 (s, 2 H) 4.19 (q, J = 7.1 Hz, 2 H) 6.98 (s, 1 H) 7.29-7.37 (m, 1 H) 7.39-7.46 (m, 2 H) 7.80-7.89 (m, 2 H). MS ESI/APCI Dual posi: 302[M + H]⁺, 324[M + Na]⁺. MS ESI/APCI Dual nega: 300[M − H]⁻, 336[M + Cl]⁻. Reference Example A-287

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.19-1.32 (m, 9 H) 2.50 (s, 2 H) 4.07-4.23 (m, 4 H) 7.30-7.35 (m, 1 H) 7.37-7.45 (m, 3 H) 7.87 (dd, J = 8.3, 1.3 Hz, 2 H). [MS ESI/APCI Dual posi: 319[M + H]⁺, 341[M + Na]⁺. Reference Example A-288

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.35 (m, 9 H) 2.52 (s, 2 H) 3.73-3.81 (m, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.38-7.51 (m, 3 H) 7.60 (s, 1 H) 7.97-8.10 (m, 2 H). MS ESI/APCI Dual posi: 303[M + H]⁺, 325[M + Na]⁺.

TABLE 18-42 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-289

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.59-0.74 (m, 2 H) 0.86-1.02 (m, 2 H) 1.25 (t, J = 7.0 Hz, 3 H) 1.80-2.01 (m, 1 H) 2.51 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.0 Hz, 2 H) 6.84 (d, J = 8.4 Hz, 1 H) 6.98-7.04 (m, 2 H) 7.04-7.12 (m, 2 H) 7.66 (dd, J = 8.4, 2.3 Hz, 1 H) 8.10 (d, J = 2.3 Hz, 1 H). MS ESI/APCI Dual posi: 341[M + H]⁺, 363[M + Na]⁺. MS ESI/APCI Dual nega: 339[M − H]⁻. Reference Example A-290

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.27 (s, 3 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.80 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.73-6.84 (m, 1 H) 7.03-7.09 (m, 2 H) 7.30-7.36 (m, 2 H) 7.45-7.54 (m, 1 H) 7.96-8.05 (m, 1 H). MS ESI/APCI Dual posi: 315[M + H]⁺, 337[M + Na]⁺. MS ESI/APCI Dual nega: 313[M − H]⁻. Reference Example A-291

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.55 (t, J = 6.5 Hz, 2 H) 2.93 (t, J = 6.5 Hz, 2 H) 3.83 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.96-7.03 (m, 1 H) 7.06-7.14 (m, 2 H) 7.35-7.43 (m, 2 H) 7.84-7.92 (m, 1 H) 8.40-8.47 (m, 1 H). MS ESI/APCI Dual posi: 369[M + H]⁺, 391[M + Na]⁺. MS ESI/APCI Dual nega: 367[M − H]⁻, 403[M + Cl]⁻. Reference Example A-292

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.32 (m, 9 H) 2.49 (s, 2 H) 3.77 (s, 2 H) 3.93 (s, 3 H) 4.14 (q, J = 7.0 Hz, 2 H) 6.46 (s, 1 H) 7.23-7.30 (m, 1 H) 7.33-7.40 (m, 2 H) 7.72-7.79 (m, 2 H). MS ESI/APCI Dual posi: 316[M + H]⁺, 338[M + Na]⁺. Reference Example A-293

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.33 (m, 9 H) 2.52 (s, 2 H) 3.78 (s, 2 H) 3.83 (s, 3 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.27 (s, 1 H) 7.33-7.50 (m, 5 H). MS ESI/APCI Dual posi: 316[M + H]⁺, 338[M + Na]⁺. Reference Example A-294

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15-1.34 (m, 9 H) 2.23 (s, 3 H) 2.50 (s, 2 H) 3.81 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.36-7.48 (m, 3 H) 7.94-8.06 (m, 2 H). MS ESI/APCI Dual posi: 317[M + H]⁺, 339[M + Na]⁺. Reference Example A-295

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.26-0.41 (m, 2 H) 0.57-0.70 (m, 2 H) 1.17 (s, 6 H) 1.20-1.26 (m, 4 H) 2.63 (s, 2 H) 3.71 (s, 2 H) 3.78 (d, J = 6.8 Hz, 2 H) 4.12 (q, J = 7.1 Hz, 2 H) 6.81-6.87 (m, 2 H) 7.17-7.22 (m, 2 H). MS ESI/APCI Dual posi: 306[M + H]⁺.

TABLE 18-43 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-296

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.46- 0.56 (m, 2 H) 0.66-0.76 (m, 2 H) 1.27 (t, J = 7.1 Hz, 3 H) 2.35 (s, 3 H) 2.49 (s, 2 H) 3.76 (s, 2 H) 4.17 (q, J = 7.0 Hz, 2 H) 6.82 (d, J = 8.4 Hz, 1 H) 6.95-7.03 (m, 2 H) 7.14-7.21 (m, 2 H) 7.63 (dd, J = 8.4, 2.5 Hz, 1 H) 8.08 (d, J = 2.5 Hz, 1 H). MS ESI/APCI Dual posi: 341[M + H]⁺. Reference Example A-297

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (s, 6 H) 1.24 (t, J = 7.1 Hz, 3 H) 2.63 (s, 2 H) 3.77 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.23-7.25 (m, 2 H) 7.44-7.46 (m, 1 H). MS ESI/APCI Dual posi: 354[M + H]⁺. Reference Example A-298

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.36 (s, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.73 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 5.01 (s, 2 H) 6.88-6.95 (m, 2 H) 7.16-7.24 (m, 4 H) 7.29-7.35 (m, 2 H). MS ESI/APCI Dual posi: 328[M + H]⁺, 350[M + Na]⁺. MS ESI/APCI Dual nega: 326[M − H]⁻. Reference Example A-299

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.03 (s, 2 H) 6.83-6.95 (m, 2 H) 7.22-7.26 (m, 2 H) 7.28-7.32 (m, 3 H) 7.42-7.45 (m, 1 H). MS ESI/APCI Dual posi: 348[M + H]⁺, 370[M + Na]⁺. MS ESI/APCI Dual nega: 346[M − H]⁻, 382[M + Cl]⁻. Reference Example A-300

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.96- 1.34 (m, 8 H) 1.58-1.65 (m, 1 H) 1.67-1.79 (m, 2 H) 1.80-1.94 (m, 2 H) 2.36-2.54 (m, 3 H) 2.90 (t, J = 6.6 Hz, 2 H) 4.14 (q, J = 7.0 Hz, 2 H). MS ESI/APCI Dual posi: 200[M + H]⁺.

TABLE 18-44 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-301

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.32 (s, 3 H) 2.40 (s, 3 H) 2.48-2.56 (m, 2 H) 2.84-2.91 (m, 2 H) 3.73 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.85 (s, 2 H) 6.92 (d, J = 8.2 Hz, 1 H) 7.18 (dd, J = 8.2, 2.2 Hz, 1 H) 7.36 (d, J = 2.2 Hz, 1 H). MS ESI/APCI Dual posi: 367[M + H]⁺, 389[M + Na]⁺. MS ESI/APCI Dual nega: 365[M − H]⁻. Reference Example A-302

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.27-0.41 (m, 2 H) 0.54-0.66 (m, 2 H) 1.15-1.33 (m, 4 H) 2.24 (s, 3 H) 2.44-2.58 (m, 2 H) 2.82- 2.97 (m, 2 H) 3.70 (s, 2 H) 3.80 (d, J = 6.7 Hz, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 6.73 (d, J = 8.1 Hz, 1 H) 6.98-7.13 (m, 2 H). MS ESI/APCI Dual posi: 292[M + H]⁺. Reference Example A-303

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.3 Hz, 2 H) 2.87 (t, J = 6.3 Hz, 2 H) 3.78 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.40-7.47 (m, 1 H) 7.53-7.60 (m, 1 H) 8.31 (d, J = 2.3 Hz, 1 H). MS ESI/APCI Dual posi: 287[M + H]⁺. Reference Example A-304

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22-1.32 (m, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.89 (s, 2 H) 4.08-4.21 (m, 2 H) 7.22-7.29 (m, 1 H) 7.77 (dd, J = 8.2, 2.3 Hz, 1 H) 8.61 (d, J = 2.3 Hz, 1 H). MS ESI/APCI Dual posi: 287[M + H]⁺. Reference Example A-305

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16-2.00 (m, 13 H) 3.52 (s, 2 H) 4.05-4.26 (m, 2 H) 7.10 (d, J = 8.4 Hz, 2 H) 7.63 (d, J = 8.4 Hz, 2 H). MS ESI/APCI Dual posi: 388[M + H]⁺. Reference Example A-306

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.67-1.81 (m, 4 H) 1.81-1.90 (m, 2 H) 2.04-2.12 (m, 2 H) 3.65 (s, 2 H) 3.74 (s, 3 H) 7.30-7.35 (m, 1 H) 7.38-7.45 (m, 4 H) 7.51-7.60 (m, 4 H). MS ESI posi: 310[M + H]⁺. Reference Example A-307

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.30-0.38 (m, 2 H) 0.59-0.68 (m, 2 H) 1.15 (d, J = 6.4 Hz, 3 H) 1.19-1.35 (m, 1 H) 2.33-2.55 (m, 2 H) 3.08-3.21 (m, 1 H) 3.67 (s, 3 H) 3.65- 3.82 (m, 2 H) 3.78 (d, J = 7.0 Hz, 2 H) 6.82- 6.89 (m, 2 H) 7.18-7.25 (m, 2 H). MS ESI/APCI Dual posi: 278[M + H]⁺.

TABLE 18-45 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-308

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J = 7.2 Hz, 3 H) 1.90-2.13 (m, 4 H) 2.41- 2.49 (m, 2 H) 3.63 (s, 2 H) 4.21 (q, J = 7.2 Hz, 2 H) 7.30-7.36 (m, 1 H) 7.39-7.46 (m, 4 H) 7.52- 7.60 (m, 4 H). MS ESI posi: 310[M + H]⁺. Reference Example A-309

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.19-1.39 (m, 6 H) 3.40 (q, J = 7.1 Hz, 1 H) 3.69 (d, J = 12.9 Hz, 1 H) 3.79-3.87 (m, 1 H) 4.21 (q, J = 7.1 Hz, 2 H) 7.00 (d, J = 8.7 Hz, 1 H) 7.06- 7.14 (m, 2 H) 7.40 (d, J = 8.7 Hz, 2 H) 7.83-7.93 (m, 1 H) 8.40-8.48 (m, 1 H). MS ESI/APCI Dual posi: 369[M + H]⁺, 391[M + Na]⁺. MS ESI/APCI Dual nega: 367[M − H]⁻. Reference Example A-310

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 6 H) 3.65 (s, 2 H) 3.75 (s, 3 H) 6.94-7.02 (m, 1 H) 7.10 (d, J = 8.5 Hz, 2 H) 7.41 (d, J = 8.7 Hz, 2 H) 7.81-7.93 (m, 1 H) 8.37-8.50 (m, 1 H). MS ESI/APCI Dual posi: 369[M + H]⁺, 391[M + Na]⁺. MS ESI/APCI Dual nega: 367[M − H]⁻. Reference Example A-311

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.26-0.40 (m, 2 H) 0.56-0.70 (m, 2 H) 1.17-1.35 (m, 1 H) 3.41 (s, 2 H) 3.62-3.88 (m, 7 H) 6.86 (d, J = 8.5 Hz, 2 H) 7.15-7.30 (m, 2 H). MS ESI/APCI Dual posi: 250[M + H]⁺, 272[M + Na]⁺. Reference Example A-312

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.27-0.42 (m, 2 H) 0.54-0.73 (m, 2 H) 1.15-1.36 (m, 7 H) 3.24-3.43 (m, 1 H) 3.54-3.65 (m, 1 H) 3.66-3.84 (m, 3 H) 4.19 (d, J = 7.1 Hz, 2 H) 6.82- 6.91 (m, 2 H) 7.22 (d, J = 8.4 Hz, 2 H). MS ESI/APCI Dual posi: 278[M + H]⁺, 300[M + Na]⁺. Reference Example A-313

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.37 (m, 2 H) 0.60-0.66 (m, 2 H) 1.18-1.33 (m, 1 H) 1.36 (s, 6 H) 3.54 (s, 2 H) 3.74 (s, 3 H) 3.78 (d, J = 7.0 Hz, 2 H) 6.85 (d, J = 8.5 Hz, 2 H) 7.23 (d, J = 8.5 Hz, 2 H). MS ESI/APCI Dual posi: 278[M + H]⁺, 300[M + Na]⁺. Reference Example A-314

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.26-0.44 (m, 2 H) 0.56-0.69 (m, 2 H) 1.06-1.32 (m, 4 H) 2.46-2.78 (m, 2 H) 3.37-3.51 (m, 1 H) 3.53-3.63 (m, 1 H) 3.78 (d, J = 6.8 Hz, 2 H) 3.97- 4.19 (m, 3 H) 6.80-6.87 (m, 2 H) 7.12-7.19 (m, 2 H) 7.23-7.37 (m, 5 H). MS ESI/APCI Dual posi: 354[M + H]⁺, 376[M + Na]⁺. MS ESI/APCI Dual nega: 352[M − H]⁻.

TABLE 18-46 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-315

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.24-0.40 (m, 2 H) 0.57-0.69 (m, 2 H) 1.18 (t, J = 7.1 Hz, 3 H) 1.22-1.35 (m, 1 H) 2.51-2.79 (m, 2 H) 3.38-3.51 (m, 1 H) 3.54-3.63 (m, 1 H) 3.78 (d, J = 7.1 Hz, 2 H) 4.02-4.17 (m, 3 H) 6.76- 6.92 (m, 2 H) 7.16 (d, J = 8.7 Hz, 2 H) 7.23-7.42 (m, 5 H). MS ESI/APCI Dual posi: 354[M + H]⁺, 376[M + Na]⁺. MS ESI/APCI Dual nega: 352[M − H]⁻. Reference Example A-316

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.30-0.38 (m, 2 H) 0.59-0.68 (m, 2 H) 1.15 (d, J = 6.4 Hz, 3 H) 1.19-1.35 (m, 1 H) 2.33-2.55 (m, 2 H) 3.08-3.21 (m, 1 H) 3.67 (s, 3 H) 3.65- 3.82 (m, 2 H) 3.78 (d, J = 7.0 Hz, 2 H) 6.82- 6.89 (m, 2 H) 7.18-7.25 (m, 2 H). MS ESI/APCI Dual posi: 278[M + H]⁺. Reference Example A-317

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.30-0.38 (m, 2 H) 0.59-0.68 (m, 2 H) 1.20-1.34 (m, 1 H) 1.64-1.71 (m, 4 H) 2.57 (s, 2 H) 3.58- 3.70 (m, 7 H) 3.79 (d, J = 7.0 Hz, 2 H) 3.85-3.95 (m, 2 H) 6.83-6.90 (m, 2 H) 7.24-7.31 (m, 2 H). MS ESI/APCI Dual posi: 334[M + H]⁺. Reference Example A-318

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.31-0.38 (m, 2 H) 0.60-0.68 (m, 2 H) 1.19-1.35 (m, 4 H) 2.96 (s, 2 H) 3.74-3.81 (m, 4 H) 4.11- 4.21 (m, 2 H) 4.53 (d, J = 6.8 Hz, 2 H) 4.66 (d, J = 6.8 Hz, 2 H) 6.82-6.90 (m, 2 H) 7.20-7.28 (m, 2 H). MS ESI/APCI Dual posi: 320[M + H]⁺. Reference Example A-319

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.40 (m, 2 H) 0.60-0.70 (m, 2 H) 1.17-1.34 (m, 1 H) 2.76-2.82 (m, 2 H) 3.48 (dd, J = 6.8, 4.9 Hz, 1 H) 3.69 (s, 3 H) 3.73 (d, J = 2.8 Hz, 2 H) 3.79 (d, J = 6.8 Hz, 2 H) 5.36-5.53 (m, 1 H) 6.87 (d, J = 8.7 Hz, 2 H) 7.14-7.24 (m, 2 H). MS ESI/APCI Dual posi: 307[M + H]⁺, 329[M + Na]⁺. Reference Example A-320

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.40 (m, 2 H) 0.58-0.70 (m, 2 H) 1.17-1.35 (m, 1 H) 2.76-2.84 (m, 2 H) 3.43-3.54 (m, 1 H) 3.69 (s, 3 H) 3.73 (d, J = 2.6 Hz, 2 H) 3.79 (d, J = 7.0 Hz, 2 H) 5.42 (br. s., 1 H) 6.80-6.94 (m, 2 H) 7.21 (d, J = 8.7 Hz, 2 H). MS ESI/APCI Dual posi: 307[M + H]⁺, 329[M + Na]⁺. Reference Example A-321

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10-1.30 (m, 10 H) 1.57-1.78 (m, 1 H) 1.80-1.91 (m, 2 H) 2.38-2.47 (m, 4 H) 2.80-2.93 (m, 2 H) 4.08-4.18 (m, 2 H) 4.70-4.81 (m, 2 H) 6.42 (t, J = 4.8 Hz, 1 H) 8.28 (d, J = 4.8 Hz, 2 H). MS ESI/APCI Dual posi: 321[M + H]⁺ ₋

TABLE 18-47 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-322

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.13-0.21 (m, 2 H) 0.51-0.59 (m, 2 H) 0.97- 1.31 (m, 12 H) 1.53-1.69 (m, 1 H) 1.77-1.89 (m, 2 H) 2.24-2.29 (m, 2 H) 2.37-2.46 (m, 4 H) 2.48-2.62 (m, 1 H) 2.94-3.06 (m, 1 H) 3.78-3.89 (m, 1 H) 4.07-4.20 (m, 2 H) 4.59-4.70 (m, 1 H). MS ESI/APCI Dual posi: 325[M + H]⁺. Reference Example A-323

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.28-0.43 (m, 2 H) 0.57-0.74 (m, 2 H) 1.12-1.33 (m, 4 H) 2.47-2.85 (m, 2 H) 3.40-3.52 (m, 1 H) 3.54-3.63 (m, 1 H) 3.78 (d, J = 7.0 Hz, 2 H) 3.98- 4.19 (m, 3 H) 6.76-6.89 (m, 2 H) 7.08-7.19 (m, 2 H) 7.29 (ddd, J = 7.8, 4.8, 0.8 Hz, 1 H) 7.73 (dt, J = 7.8, 2.0 Hz, 1 H) 8.48-8.62 (m, 2 H). MS ESI/APCI Dual posi: 355[M + H]⁺, 377[M + Na]⁺. Reference Example A-324

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.28-0.43 (m, 2 H) 0.57-0.70 (m, 2 H) 1.13-1.33 (m, 4 H) 2.53-2.81 (m, 2 H) 3.41-3.52 (m, 1 H) 3.53-3.64 (m, 1 H) 3.78 (d, J = 6.8 Hz, 2 H) 4.02- 4.18 (m, 3 H) 6.78-6.92 (m, 2 H) 7.14 (d, J = 8.7 Hz, 2 H) 7.26-7.34 (m, 1 H) 7.73 (dt, J = 7.9, 1.9 Hz, 1 H) 8.48-8.63 (m, 2 H). MS ESI/APCI Dual posi: 355[M + H]⁺, 377[M + Na]⁺. Reference Example A-325

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.30-0.39 (m, 2 H) 0.58-0.68 (m, 2 H) 1.19-1.34 (m, 1 H) 2.42 (d, J = 6.4 Hz, 2 H) 2.68-2.91 (m, 2 H) 3.21-3.32 (m, 1 H) 3.65 (s, 3 H) 3.71-3.81 (m, 4 H) 6.78-6.86 (m, 2 H) 7.09-7.34 (m, 7 H). MS ESI/APCI Dual posi: 354[M + H]⁺. Reference Example A-326

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.30-0.39 (m, 2 H) 0.58-0.68 (m, 2 H) 1.19-1.34 (m, 1 H) 2.42 (d, J = 6.4 Hz, 2 H) 2.68-2.91 (m, 2 H) 3.21-3.32 (m, 1 H) 3.65 (s, 3 H) 3.71-3.81 (m, 4 H) 6.78-6.86 (m, 2 H) 7.09-7.34 (m, 7 H). MS ESI/APCI Dual posi: 354[M + H]⁺. Reference Example A-327

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.20-0.49 (m, 2 H) 0.56-0.72 (m, 2 H) 1.10-1.63 (m, 9 H) 1.91-2.18 (m, 2 H) 2.64 (s, 2 H) 3.68 (s, 5 H) 3.74-3.84 (m, 2 H) 6.84 (d, J = 8.7 Hz, 2 H) 7.18 (d, J = 8.7 Hz, 2 H). MS ESI/APCI Dual posi: 332[M + H]⁺, 354[M + Na]⁺. Reference Example A-328

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.25-0.40 (m, 2 H) 0.56-0.69 (m, 2 H) 1.17-1.76 (m, 11 H) 2.52 (s, 2 H) 3.60 (s, 2 H) 3.67 (s, 3 H) 3.78 (d, J = 6.8 Hz, 2 H) 6.85 (d, J = 8.7 Hz, 2 H). MS ESI/APCI Dual posi: 332[M + H]⁺, 354[M + Na]⁺.

TABLE 18-48 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-329

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm ppm 1.18-1.33 (m, 9 H) 2.50 (s, 2 H) 3.67 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.48 (s, 2 H) 6.87 (d, J = 8.7 Hz, 2 H) 7.31 (d, J = 8.7 Hz, 2 H). MS ESI/APCI Dual posi: 309[M + H]⁺, 331[M + Na]⁺. MS ESI/APCI Dual nega: 307[M − H]⁻. Reference Example A-330

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 6 H) 1.18-1.45 (m, 4 H) 1.59-1.79 (m, 4 H) 1.88-2.01 (m, 2 H) 2.35-2.44 (m, 4 H) 2.82- 2.94 (m, 2 H) 3.48 (s, 2 H) 4.12 (q, J = 7.2 Hz, 2 H) 7.18-7.36 (m, 5 H). MS ESI/APCI Dual posi: 333[M + H]⁺. Reference Example A-331

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.39 (m, 2 H) 0.58-0.67 (m, 2 H) 0.88-0.92 (m, 6 H) 1.19-1.34 (m, 1 H) 1.79-1.95 (m, 1 H) 2.27-2.50 (m, 2 H) 2.80-2.92 (m, 1 H) 3.67 (s, 3 H) 3.70 (s, 2 H) 3.75-3.82 (m, 2 H) 6.84 (d, J = 8.7 Hz, 2 H) 7.18-7.26 (m, 2 H). MS ESI/APCI Dual posi: 306[M + H]⁺, 328[M + Na]⁺. Reference Example A-332

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.39 (m, 2 H) 0.59-0.69 (m, 2 H) 0.85-1.00 (m, 6 H) 1.18-1.35 (m, 1 H) 1.79-1.95 (m, 1 H) 2.26-2.50 (m, 2 H) 2.81-2.95 (m, 1 H) 3.67 (s, 3 H) 3.70 (s, 2 H) 3.78 (d, J = 6.8 Hz, 2 H) 6.85 (d, J = 8.4 Hz, 2 H) 7.22 (d, J = 8.4 Hz, 2 H). MS ESI/APCI Dual posi: 306[M + H]⁺, 328[M + Na]⁺. Reference Example A-333

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.28-0.39 (m, 2 H) 0.56-0.63 (m, 2 H) 1.19-1.36 (m, 10 H) 2.50 (s, 2 H) 3.63 (s, 2 H) 4.02-4.20 (m, 4 H) 6.73 (d, J = 8.5 Hz, 1 H) 7.61 (dd, J = 8.5, 2.4 Hz, 1 H) 8.02-8.07 (m, 1 H). MS ESI/APCI Dual posi: 307[M + H]⁺, 329[M + Na]⁺. Reference Example A-334

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.38 (m, 2 H) 0.59-0.69 (m, 2 H) 1.15-1.35 (m, 1 H) 2.29-2.45 (m, 1 H) 2.62-2.75 (m, 1 H) 3.57-3.70 (m, 1 H) 3.70-3.74 (m, 2 H) 3.79 (d, J = 6.8 Hz, 2 H) 4.05-4.17 (m, 1 H) 4.29-4.40 (m, 1 H) 6.87 (d, J = 8.9 Hz, 2 H) 7.20 (d, 8.9 Hz, 2 H). MS ESI/APCI Dual posi: 284[M + Na]⁺. MS ESI/APCI Dual nega: 260[M − H]⁻. Reference Example A-335

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.28-0.39 (m, 2 H) 0.58-0.69 (m, 2 H) 1.17-1.35 (m, 1 H) 2.38 (dd, J = 17.5, 4.7 Hz, 1 H) 2.65- 2.73 (m, 1 H) 3.62-3.70 (m, 1 H) 3.73 (d, J = 1.4 Hz, 2 H) 3.79 (d, J = 7.0 Hz, 2 H) 4.10 (dd, J = 9.5, 4.1 Hz, 1 H) 4.36 (dd, J = 9.5, 6.1 Hz, 1 H) 6.81-6.92 (m, 2 H) 7.15-7.24 (m, 2 H). MS ESI/APCI Dual posi: 284[M + Na]⁺. MS ESI/APCI Dual nega: 260[M − Na]⁻. Reference Example A-336

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17 (s, 6 H) 1.22-1.31 (m, 3 H) 2.42 (s, 2 H) 2.71-2.81 (m, 1 H) 3.79-3.86 (m, 2 H) 4.07-4.27 (m, 6 H) 6.47-6.52 (m, 1 H) 8.28-8.32 (m, 2 H). MS ESI/APCI Dual posi: 293[M + H]⁺.

TABLE 18-49 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-337

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.34-0.42 (m, 2 H) 0.59-0.67 (m, 2 H) 1.19-1.28 (m, 9 H) 1.28-1.41 (m, 1 H) 2.49 (s, 2 H) 3.98 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.32 (d, J = 7.2 Hz, 2 H) 6.94 (d, J = 9.0 Hz, 1 H) 7.50 (d, J = 9.0 Hz, 1 H). MS ESI/APCI Dual posi: 308[M + H]⁺. Reference Example A-338

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.38 (m, 2 H) 0.59-0.68 (m, 2 H) 1.18-1.33 (m, 1 H) 2.48-2.51 (m, 2 H) 3.14-3.27 (m, 1 H) 3.32 (s, 3 H) 3.34-3.47 (m, 2 H) 3.67 (s, 3 H) 3.70-3.82 (m, 4 H) 6.79-6.92 (m, 2 H) 7.17-7.28 (m, 2 H). MS ESI/APCI Dual posi: 308[M + H]⁺, 330[M + Na]⁺. MS ESI/APCI Dual nega: 306[M − H]⁻. Reference Example A-339

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.31-0.40 (m, 2 H) 0.57-0.67 (m, 2 H) 1.19-1.36 (m, 10 H) 2.51 (s, 2 H) 3.82 (s, 2 H) 4.10-4.17 (m, 4 H) 8.08 (d, J = 1.4 Hz, 1 H) 8.19 (d, J = 1.4 Hz, 1 H). MS ESI/APCI Dual posi: 308[M + H]⁺. Reference Example A-340

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.27-0.39 (m, 2 H) 0.58-0.68 (m, 2 H) 1.18-1.35 (m, 1 H) 2.15 (s, 6 H) 2.16-2.28 (m, 2 H) 2.31- 2.45 (m, 2 H) 2.49-2.56 (m, 1 H) 3.03-3.17 (m, 1 H) 3.67 (s, 3 H) 3.74-3.83 (m, 3 H) 6.85 (d, J = 8.7 Hz, 2 H) 7.16-7.24 (m, 2 H). MS ESI/APCI Dual posi: 321[M + H]⁺. Reference Example A-341

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9 H) 1.49-1.57 (m, 2 H) 1.64-1.76 (m, 2 H) 2.49-2.57 (m, 2 H) 3.27-3.40 (m, 2 H) 3.61- 3.78 (m, 7 H) 7.22-7.26 (m, 1 H) 7.29-7.34 (m, 2 H) 7.35-7.39 (m, 2 H). MS ESI/APCI Dual posi: 363[M + H]⁺, 385[M + Na]⁺. Reference Example A-342

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.06 (s, 6 H) 0.90 (s, 9 H) 1.18 (s, 6 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.42 (s, 2 H) 2.66 (t, J = 5.8 Hz, 2 H) 3.70 (t, J = 5.8 Hz, 2 H) 4.13 (q, J = 7.1 Hz, 2 H). Reference Example A-343

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.31- 1.46 (m, 10 H) 2.56 (s, 2 H) 2.86-2.96 (m, 2 H) 3.42 (s, 3 H) 4.12-4.19 (m, 2 H) 7.41- 7.47 (m, 3 H) 7.59-7.66 (m, 2 H) 9.12 (br. s, 2 H). MS ESI/APCI Dual posi: 276[M + H]⁺. HCl

TABLE 18-50 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-344

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9 H) 1.51-1.60 (m, 2 H) 1.67-1.78 (m, 2 H) 2.52-2.60 (m, 2 H) 3.31-3.42 (m, 2 H) 3.64- 3.79 (m, 7 H) 7.32-7.36 (m, 1 H) 7.41-7.47 (m, 4 H) 7.53-7.62 (m, 4 H). MS ESI/APCI Dual posi: 439[M + H]⁺. Reference Example A-345

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 1.32-1.61 (m, 10 H) 2.61 (s, 2 H) 3.14 (s, 2 H) 3.64 (s, 3 H) 4.33 (s, 2 H) 7.32-7.41 (m, 1 H) 7.42-7.51 (m, 2 H) 7.61-7.68 (m, 4 H) 7.71- 7.77 (m, 2 H). MS ESI/APCI Dual posi: 352[M + H]⁺. HCl Reference Example A-346

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.2 Hz, 3 H) 1.45 (s, 9 H) 3.79 (s, 2 H) 3.85 (d, J = 9.1 Hz, 2 H) 3.94 (d, J = 9.1 Hz, 2 H) 4.17 (q, J = 7.2 Hz, 2 H) 7.32-7.37 (m, 1 H) 7.39-7.47 (m, 4 H) 7.53-7.62 (m, 4 H). MS ESI/APCI Dual posi: 425[M + H]⁺, 447[M + Na]⁺. MS ESI/APCI Dual nega: 459[M + Cl]⁻. Reference Example A-347

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.02-2.08 (m, 1 H) 2.39-2.48 (m, 1 H) 2.55-2.64 (m, 1 H) 2.72-2.91 (m, 2 H) 3.45-3.50 (m, 2 H) 3.72 (s, 3 H) 3.75-3.80 (m, 2 H) 5.63 (br. s., 1 H) 7.35-7.47 (m, 5 H) 7.52-7.61 (m, 4 H). MS ESI/APCI Dual posi: 339[M + H]⁺, 361[M + Na]⁺. MS ESI/APCI Dual nega: 373[M + Cl]⁻. Reference Example A-348

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.43-2.53 (m, 1 H) 2.62-2.70 (m, 1 H) 2.74-2.90 (m, 5 H) 3.41-3.52 (m, 2 H) 3.68-3.77 (m, 5 H) 7.32-7.47 (m, 5 H) 7.52-7.61 (m, 4 H). MS ESI/APCI Dual posi: 353[M + H]⁺, 375[M + Na]⁺. Reference Example A-349

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.55 (t, J = 6.4 Hz, 2 H) 2.93 (t, J = 6.4 Hz, 2 H) 3.88 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.47-7.51 (m, 2 H) 7.53-7.57 (m, 2 H) 8.95 (s, 2 H) 9.20 (s, 1 H). MS ESI/APCI Dual posi: 286[M + H]. Reference Example A-350

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.84-0.91 (m, 3 H) 1.21-1.34 (m, 15 H) 1.42- 1.57 (m, 2 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.63 (t, J = 7.1 Hz, 2 H) 2.90 (t, J = 6.5 Hz, 2 H) 4.15 (q, J = 7.1 Hz, 2 H). MS ESI/APCI Dual posi: 244[M + H]⁺.

TABLE 18-51 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-351

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 3.46 (s, 2 H) 3.74 (s, 3 H) 3.85 (s, 2 H) 7.28-7.49 (m, 5 H) 7.52-7.63 (m, 4 H). MS ESI/APCI Dual posi: 256[M + H]⁺. Reference Example A-352

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.90 (d, J = 6.7 Hz, 6 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.66-1.82 (m, 1 H) 2.42 (d, J = 6.8 Hz, 2 H) 2.48- 2.54 (m, 2 H) 2.83-2.89 (m, 2 H) 4.14 (q, J = 7.1 Hz, 2 H). MS ESI/APCI Dual posi: 174[M + H]⁺. Reference Example A-353

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.2 Hz, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.90 (t, J = 6.4 Hz, 2 H) 3.83 (s, 2 H) 4.15 (q, J = 7.2 Hz, 2 H) 8.72 (s, 2 H) 9.13 (s, 1 H). MS ESI/APCI Dual posi: 210[M + H]⁺. Reference Example A-354

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.2 Hz, 3 H) 1.46-1.65 (m, 6 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.89 (t, J = 6.4 Hz, 2 H) 3.29- 3.39 (m, 2 H) 3.66-3.75 (m, 2 H) 3.82 (s, 2 H) 4.15 (q, J = 7.2 Hz, 2 H) 7.33-7.37 (m, 4 H). MS ESI/APCI Dual posi: 319[M + H]⁺, 341[M + Na]⁺. Reference Example A-355

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.98 (t, J = 7.4 Hz, 3 H) 1.25 (t, J = 7.2 Hz, 3 H) 1.60-1.67 (m, 2 H) 2.51 (t, J = 6.4 Hz, 2 H) 2.87 (t, J = 6.4 Hz, 2 H) 3.39-3.44 (m, 2 H) 3.83 (s, 2 H) 4.13 (q, J = 7.2 Hz, 2 H) 6.03-6.11 (m, 1 H) 7.36-7.39 (m, 2 H) 7.66-7.76 (m, 2 H). MS ESI/APCI Dual posi: 293[M + H]⁺, 315[M + Na]⁺. Reference Example A-356

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.34 (d, J = 6.9 Hz, 3 H) 3.39-3.47 (m, 1 H) 3.67- 3.77 (m, 4 H) 3.81-3.88 (m, 1 H) 7.31-7.37 (m, 1 H) 7.38-7.47 (m, 4 H) 7.52-7.61 (m, 4 H). MS ESI/APCI Dual posi: 270[M + H]⁺, 292[M + Na]⁺. Reference Example A-357

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.31 (m, 3 H) 1.38 (s, 6 H) 3.67 (s, 2 H) 4.18-4.24 (m, 2 H) 7.30-7.36 (m, 1 H) 7.39-7.46 (m, 4 H) 7.52-7.60 (m, 4 H). MS ESI/APCI Dual posi: 298[M + H]⁺, 320[M + Na]⁺.

TABLE 18-52 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-358

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J = 7.0 Hz, 3 H) 1.37-1.53 (m, 4 H) 1.60- 1.68 (m, 2 H) 1.71-1.81 (m, 2 H) 1.90-1.99 (m, 2 H) 3.63 (s, 2 H) 4.21 (q, J = 7.0 Hz, 2 H) 7.31- 7.36 (m, 1 H) 7.38-7.46 (m, 4 H) 7.52-7.60 (m, 4 H). MS ESI/APCI Dual posi: 338[M + H]⁺. Reference Example A-359

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.70 (s, 3 H) 3.77 (s, 2 H) 4.43 (s, 1 H) 7.28-7.49 (m, 10 H) 7.51-7.62 (m, 4 H). MS ESI/APCI Dual posi: 332[M + H]⁺, 354[M + Na]⁺. Reference Example A-360

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.3 Hz, 2 H) 2.89 (t, J = 6.3 Hz, 2 H) 3.04 (s, 3 H) 3.90 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.55 (d, J = 8.4 Hz, 2 H) 7.90 (d, J = 8.4 Hz, 2 H). MS ESI/APCI Dual posi: 286[M + H]⁺. Reference Example A-361

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.27 (m, 3 H) 1.31-1.74 (m, 10 H) 2.50 (s, 2 H) 3.04 (s, 3 H) 3.78 (s, 2 H) 4.05-4.19 (m, 2 H) 7.61 (d, J = 8.4 Hz, 2 H) 7.88 (d, J = 8.4 Hz, 2 H). MS ESI/APCI Dual posi: 354[M + H]⁺. Reference Example A-362

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J = 7.1 Hz, 3 H) 1.36-2.03 (m, 10 H) 3.65 (s, 2 H) 4.22 (q, J = 7.1 Hz, 2 H) 7.41-7.50 (m, 2 H) 7.51-7.60 (m, 2 H) 7.63-7.74 (m, 4 H). MS ESI/APCI Dual posi: 406[M + H]⁺, 428[M + Na]⁺. Reference Example A-363

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17-2.03 (m, 22 H) 3.62 (s, 2 H) 4.21 (q, J = 7.3 Hz, 2 H) 7.33-7.62 (m, 8 H). MS ESI/APCI Dual posi: 394[M + H]⁺, 416[M + Na]⁺. Reference Example A-364

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17-1.34 (m, 7 H) 1.35-1.58 (m, 4 H) 2.01-2.10 (m, 2 H) 2.65 (s, 2 H) 3.05 (s, 3 H) 3.86 (s, 2 H) 4.17 (q, J = 7.0 Hz, 2 H) 7.51 (d, J = 8.4 Hz, 2 H) 7.88 (d, J = 8.4 Hz, 2 H). MS ESI/APCI Dual posi: 354[M + H]⁺, 376[M + Na]⁺.

TABLE 18-53 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-365

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.00-1.18 (m, 1 H) 1.20-1.80 (m, 16 H) 1.81- 2.01 (m, 4 H) 2.24-2.35 (m, 1 H) 2.38-2.56 (m, 1 H) 4.18 (q, J = 7.0 Hz, 2 H) 7.08-7.37 (m, 5 H). MS ESI/APCI Dual posi: 344[M + H]⁺, 366[M + Na]⁺. Reference Example A-366

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.35 (s, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.56 (s, 3 H) 2.88 (t, J = 6.4 Hz, 2 H) 3.72 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.17 (d, J = 8.4 Hz, 1 H) 7.37 (dd, J = 8.4, 2.8 Hz, 1 H) 7.54- 7.57 (m, 1 H) 7.84-7.87 (m, 1 H) 8.34 (d, J = 2.8 Hz, 1 H). MS ESI/APCI Dual posi: 330[M + H]⁺, 352[M + Na]⁺. Reference Example A-367

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23-1.41 (m, 3 H) 3.21 (t, J = 13.3 Hz, 2 H) 3.87- 3.97 (m, 2 H) 4.33 (q, J = 7.1 Hz, 2 H) 7.42 (d, J = 7.9 Hz, 2 H) 7.59 (d, J = 7.9 Hz, 2 H). MS ESI/APCI Dual posi: 312[M + H]⁺, 334[M + Na]⁺. Reference Example A-368

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.59 (s, 9 H) 2.44-2.58 (m, 2 H) 2.82-2.94 (m, 2 H) 3.86 (s, 2 H) 4.09- 4.21 (m, 2 H) 7.31-7.42 (m, 2 H) 7.90-7.98 (m, 2 H). MS ESI/APCI Dual posi: 308[M + H]⁺, 330[M + Na]⁺. Reference Example A-369

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.58 (t, J = 6.5 Hz, 2 H) 2.98 (t, J = 6.5 Hz, 2 H) 4.01 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 7.35-7.50 (m, 2 H) 7.81-7.95 (m, 2 H) 8.61-8.70 (m, 1 H) 8.73-8.89 (m, 2 H). MS ESI/APCI Dual posi: 286[M + H]⁺, 308[M + Na]⁺. Reference Example A-370

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.84-2.96 (m, 2 H) 3.68 (s, 2 H) 3.87 (s, 3 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.31 (s, 1 H) 7.41 (s, 1 H). MS ESI/APCI Dual posi: 212[M + H]⁺, 234[M + Na]⁺. Reference Example A-371

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.2 Hz, 2 H) 2.90 (t, J = 6.2 Hz, 2 H) 3.93 (d, J = 0.6 Hz, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 8.88 (s, 2 H). MS ESI/APCI Dual posi: 278[M + H]⁺, 300[M + Na]⁺.

TABLE 18-54 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-372

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.60 (s, 9 H) 2.47-2.57 (m, 2 H) 2.59 (s, 3 H) 2.92 (t, J = 6.7 Hz, 2 H) 3.67 (d, J = 0.9 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.18 (s, 1 H). MS ESI/APCI Dual posi: 312[M + H]⁺, 334[M + Na]⁺. MS ESI/APCI Dual nega: 310[M − H]⁻. Reference Example A-373

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.51 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.39-3.46 (m, 4 H) 3.76-3.83 (m, 4 H) 3.85 (d, J = 0.9 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.00 (t, J = 0.9 Hz, 1 H). MS ESI/APCI Dual posi: 300[M + H]⁺, 322[M + Na]⁺. Reference Example A-374

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.19-1.32 (m, 3 H) 2.38-2.45 (m, 3 H) 2.49-2.58 (m, 2 H) 2.98 (t, J = 6.5 Hz, 2 H) 3.98-4.10 (m, 2 H) 4.10- 4.21 (m, 2 H) 6.75-6.88 (m, 1 H). MS ESI/APCI Dual posi: 229[M + H]⁺, 251[M + Na]⁺. Reference Example A-375

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.16-1.31 (m, 3 H) 2.35 (s, 3 H) 2.46-2.64 (m, 6 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.11-3.26 (m, 4 H) 3.72 (s, 2 H) 4.07-4.19 (m, 2 H) 6.80-6.97 (m, 2 H) 7.13-7.25 (m, 2 H). MS ESI/APCI Dual posi: 328[M + Na]⁺. Reference Example A-376

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.88- 2.01 (m, 2 H) 2.26 (s, 6 H) 2.39-2.58 (m, 4 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.73 (s, 2 H) 4.00 (t, J = 6.5 Hz, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 6.80-6.90 (m, 2 H) 7.17-7.25 (m, 2 H) MS ESI/APCI Dual posi: 309[M + H]⁺, 331[M + Na]⁺. Reference Example A-377

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.19-1.30 (m, 3 H) 2.10 (s, 3 H) 2.45-2.56 (m, 2 H) 2.83-2.92 (m, 2 H) 3.74 (s, 2 H) 4.03-4.20 (m, 4 H) 4.37- 4.48 (m, 2 H) 6.87 (d, J = 8.7 Hz, 2 H) 7.24 (d, J = 8.7 Hz, 2 H). MS ESI/APCI Dual posi: 310[M + H]⁺. Reference Example A-378

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.34 (s, 6 H) 2.53-2.67 (m, 4 H) 2.82-2.93 (m, 2 H) 3.51-3.63 (m, 2 H) 3.85 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.38 (d, J = 8.5 Hz, 2 H) 7.78 (d, J = 8.5 Hz, 2 H). MS ESI/APCI Dual posi: 322[M + H]⁺, 344[M + Na]⁺. MS ESI/APCI Dual nega: 320[M − H]⁻.

TABLE 18-55 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-379

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 1.49 (s, 9 H) 2.47-2.57 (m, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.50 (s, 2 H) 6.80-6.91 (m, 2 H) 7.18-7.25 (m, 2 H). MS ESI/APCI Dual posi: 338[M + H]⁺, 360[M + Na]⁺. MS ESI/APCI Dual nega: 336[M − H]⁻. Reference Example A-380

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.10 (s, 3 H) 2.45-2.61 (m, 2 H) 2.83-2.94 (m, 2 H) 3.73 (q, J = 5.5 Hz, 2 H) 3.85 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.25- 4.35 (m, 2 H) 6.43-6.60 (m, 1 H) 7.40 (d, J = 8.5 Hz, 2 H) 7.73 (d, J = 8.5 Hz, 2 H). MS ESI/APCI Dual posi: 337[M + H]⁺, 359[M + Na]⁺. Reference Example A-381

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.50- 2.56 (m, 2 H) 2.89 (t, J = 6.4 Hz, 2 H) 3.86 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.76 (d, J = 4.8 Hz, 2 H) 7.16-7.25 (m, 1 H) 7.33 (d, J = 7.8 Hz, 1 H) 7.41 (d, J = 8.4 Hz, 2 H) 7.56 (br. s., 1 H) 7.64- 7.75 (m, 1 H) 7.79-7.87 (m, 2 H) 8.57 (dt, J = 5.0, 0.9 Hz, 1 H). MS ESI/APCI Dual posi: 342[M + H]⁺, 364[M + Na]⁺. MS ESI/APCI Dual nega: 340[M − H]⁻. Reference Example A-382

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.85-2.93 (m, 2 H) 3.10 (t, J = 6.4 Hz, 2 H) 3.79-3.95 (m, 4 H) 4.06-4.23 (m, 2 H) 7.11-7.24 (m, 2 H) 7.33-7.41 (m, 2 H) 7.45-7.56 (m, 1 H) 7.58-7.67 (m, 1 H) 7.68-7.77 (m, 2 H) 8.51-8.60 (m, 1 H). MS ESI/APCI Dual posi: 356[M + H]⁺, 378[M + Na]⁺. MS ESI/APCI Dual nega: 354[M − H]⁻. Reference Example A-383

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.98- 2.14 (m, 2 H) 2.34-2.43 (m, 2 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.83-2.92 (m, 2 H) 3.44-3.68 (m, 6 H) 3.84 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.16-7.25 (m, 1 H) 7.33-7.41 (m, 2 H) 7.69-7.81 (m, 2 H). MS ESI/APCI Dual posi: 362[M + H]⁺, 384[M + Na]⁺. MS ESI/APCI Dual nega: 360[M − H]⁻. Reference Example A-384

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.51 (s, 9 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.89 (t, J = 6.4 Hz, 2 H) 3.85 (s, 2 H) 4.08- 4.21 (m, 4 H) 6.59-6.67 (m, 1 H) 7.36- 7.43 (m, 2 H) 7.74-7.80 (m, 2 H). MS ESI/APCI Dual posi: 365[M + H]⁺, 387[M + Na]⁺. MS ESI/APCI Dual nega: 363[M − H]⁻. Reference Example A-385

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 0.76-0.92 (m, 2 H) 1.15-1.37 (m, 4 H) 1.66-1.76 (m, 1 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.58-2.74 (m, 2 H) 2.84- 3.00 (m, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.83-7.09 (m, 4 H). MS ESI/APCI Dual posi: 266[M + H]⁺.

TABLE 18-56 Com- Salt pound infor- No. Structure Analytical Data mation Reference Example A-386

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.56 (t, J = 6.6 Hz, 2 H) 2.91-2.98 (m, 2 H) 3.92 (s, 2 H) 4.15 (d, J = 7.1 Hz, 2 H) 6.94 (d, J = 9.0 Hz, 2 H) 7.22-7.35 (m, 4 H) 8.31-8.36 (m, 1 H). MS ESI/APCI Dual posi: 335[M + H]⁺, 357[M + Na]⁺. MS ESI/APCI Dual nega: 333[M − H]⁻. Reference Example A-387

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.48- 2.55 (m, 2 H) 2.84-2.93 (m, 2 H) 3.76 (s, 2 H) 3.79 (s, 3 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.64-6.78 (m, 3 H) 6.83-6.90 (m, 1 H) 7.25-7.33 (m, 1 H) 7.62-7.76 (m, 1 H) 8.07-8.19 (m, 1 H). MS ESI/APCI Dual posi: 331[M + H]⁺, 353[M + Na]⁺. MS ESI/APCI Dual nega: 329[M − H]⁻. Reference Example A-388

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 3.80 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.92-7.03 (m, 2 H) 7.20-7.28 (m, 2 H) 7.31-7.38 (m, 2 H) 8.10-8.19 (m, 1 H). MS ESI/APCI Dual posi: 335[M + H]⁺, 357[M + Na]⁺. MS ESI/APCI Dual nega: 333[M − H]⁻. Reference Example A-389

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.57 (t, J = 6.5 Hz, 2 H) 2.96 (t, J = 6.5 Hz, 2 H) 3.94 (s, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 6.98-7.10 (m, 2 H) 7.30-7.41 (m, 2 H) 7.60 (d, J = 8.5 Hz, 2 H) 8.35- 8.43 (m, 1 H). MS ESI/APCI Dual posi: 369[M + H]⁺, 391[M + Na]⁺. MS ESI/APCI Dual nega: 367[M − H]⁻. Reference Example A-390

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.82- 2.03 (m, 4 H) 2.33-2.51 (m, 2 H) 2.89 (s, 2 H) 3.78 (s, 2 H) 4.12-4.25 (m, 2 H) 7.22-7.30 (m, 2 H) 7.42-7.49 (m, 1 H). MS ESI/APCI Dual posi: 366[M + H]⁺. Reference Example A-391

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 1.16-1.31 (m, 9 H) 2.68 (s, 2 H) 3.83 (s, 2 H) 3.93-4.02 (m, 3 H) 4.08-4.19 (m, 2 H) 6.78-6.85 (m, 1 H) 7.35-7.51 (m, 4 H) 7.74-7.82 (m, 1 H) 8.35-8.42 (m, 1 H). MS ESI/APCI Dual posi: 343[M + H]⁺, 365[M + Na]⁺. Reference Example A-392

¹H NMR (300 MHz, CHLOROFORM- d) δ ppm 0.73-0.81 (m, 4 H) 1.18 (s, 6 H) 1.20-1.27 (m, 3 H) 2.62-2.67 (m, 2 H) 3.67-3.77 (m, 3 H) 4.07-4.17 (m, 2 H) 6.95-7.02 (m, 2 H) 7.18-7.25 (m, 2 H). MS ESI/APCI Dual posi: 292[M + H]⁺. MS ESI/APCI Dual nega: 290[M − H]−.

TABLE 18-57 Compound Salt No. Structure Analytical Data information Reference Example A-393

¹H HMR (300 MHz, CHLOROFORM-d) δ ppm 0.33-0.42 (m, 2 H) 0.57-0.70 (m, 2 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.26-1.39 (m, 1 H) 2.47-2.56 (m, 2 H) 2.81-2.92 (m, 2 H) 3.71 (s, 2 H) 3.87 (d, J = 6.7 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.86 (d, J = 8.4 Hz, 1 H) 7.13 (dd, J = 8.4, 2.1 Hz, 1 H) 7.33 (d, J = 2.1 Hz. 1 H). MS ESI/APCI Dual posi: 312[M + H]⁺. Reference Example A-394

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17-1.30 (m, 3 H) 1.85-2.03 (m, 4 H) 2.30-2.50 (m, 2 H) 2.93 (s, 2 H) 3.97 (s, 3 H) 4.08-4.22 (m, 2 H) 4.75 (s, 2 H) 6.78-6.85 (m, 1 H) 7.35-7.52 (m, 4 H) 7.75-7.83 (m, 1 H) 8.35-8.41 (m, 1 H). MS ESI/APCI Dual posi: 355[M + H]⁺. Reference Example A-395

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.62-0.72 (m, 2 H) 0.89-0.98 (m, 2 H) 1.18 (s, 6 H) 1.23 (t, J = 7.1 Hz, 3 H) 1.81-1.94 (m, 1 H) 2.64 (s, 2 H) 3.74 (s, 2 H) 4.06-4.17 (m, 2 H) 6.98-7.05 (m, 2 H) 7.15-7.22 (m, 2 H). MS ESI/APCI Dual posi: 276[M + H]⁺. Reference Example A-396

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.71-0.82 (m, 4 H) 1.21-1.29 (m, 3 H) 1.81-2.03 (m, 4 H) 2.30-2.49 (m, 2 H) 2.89 (s, 2 H) 3.65-3.79 (m, 3 H) 4.16 (q, J = 7.0 Hz, 2 H) 6.95-7.02 (m, 2 H) 7.18-7.25 (m, 2 H). MS ESI/APCI Dual posi: 304[M + H]⁺, 326[M + Na]⁺. Reference Example A-397

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.37 (s, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.01 (s, 2 H) 6.90-6.96 (m, 2 H) 7.10-7.16 (m, 1 H) 7.19-7.28 (m, 5 H). MS ESI/APCI Dual posi: 328[M + H]⁺, 350[M + Na]⁺. MS ESI/APCI Dual nega: 326[M − H]⁻. Reference Example A-398

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.55 (t, J = 6.4 Hz, 2 H) 2.87-2.97 (m, 2 H) 3.82 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.99-7.08 (m, 2 H) 7.27-7.43 (m, 3 H) 7.61 (d, J = 8.5 Hz, 1 H) 8.42-8.50 (m, 1 H). MS ESI/APCI Dual posi: 369[M + H]⁺, 391[M + Na]⁺. MS ESI/APCI Dual nega: 367[M − H]⁻. Reference Example A-399

¹H NMR (300-MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.36 (s, 3 H) 2.48-2.56 (m, 2 H) 2.83-2.92 (m, 2 H) 3.75 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.82-6.99 (m, 2 H) 7.10-7.27 (m, 2 H) 7.70 (dd, J = 8.4, 2.5 Hz, 1 H) 8.10 (dd, J = 2.5, 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 349[M + H]⁺, 371[M + Na]⁺. MS.ESI/APCI Dual nega: 347[M − H]⁻.

TABLE 18-58 Compound Salt No. Structure Analytical Data information Reference Example A-400

¹H HMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2 26 (d, J = 1.9 Hz, 3 H) 2.46-2.57 (m, 2 H) 2.83-2.92 (m, 2 H) 3.76 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.76-6.94 (m, 3 H) 7.11-7.22 (m, 1 H) 7.70 (dd, J = 8.4, 2.5 Hz, 1 H) 8.10 (dd, J = 2.5, 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 333[M + H]⁺, 355[M + Na]⁺. MS ESI/APCI Dual nega: 331[M − H]⁻. Reference Example A-401

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.31 (m, 3 H) 2.27 (d, J = 2.0 Hz, 3 H) 2.46-2.57 (m, 2 H) 2.83-2.92 (m, 2 H) 3.75 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.78-7.08 (m, 4 H) 7.69 (dd, J = 8.4, 2.5 Hz, 1 H) 8.04-8.12 (m, 1 H). MS ESI/APCI Dual posi: 333[M + H]⁺, 355[M + Na]⁺. MS ESI/APCI Dual nega: 331[M − H]⁻. Reference Example A-402

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2 52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.16 (s, 2 H) 6.92-6.97 (m, 2 H) 7.23-7.30 (m, 4 H) 7.37-7.42 (m, 1 H) 7.53-7.58 (m, 1 H). MS ESI/APCI Dual posi: 348[M + H]⁺, 370[M + Na]⁺. MS ESI/APCI Dual nega: 346[M − H]⁻. Reference Example A-403

¹H HMR (300 MHz, CHLOROFORM-d) δ ppm 0.38-0.45 (m, 2 H) 0.49-0.58 (m, 2 H) 1.20-1.30 (m, 6 H) 1.61-1.71 (m, 1 H) 2.51 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.68-3.75 (m, 4 H) 4.13 (q, J = 7.0 Hz, 2 H) 6.81-6.89 (m, 2 H) 7.15-7.24 (m, 2 H). MS ESI/APCI Dual posi: 292[M + H]⁺. Reference Example A-404

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21-1.31 (m, 3 H) 2.05-2.32 (m, 4 H) 2.35-2.62 (m, 3 H) 2.83 (d, J = 7.6 Hz, 2 H) 2.88-2.96 (m, 2 H) 3.42-3.67 (m, 1 H) 4.04-4.24 (m, 2 H) 6.89-7.05 (m, 2 H) 7.09-7.25 (m, 2 H). MS ESI/APCI Dual posi: 280[M + H]⁺. Reference Example A-405

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.75 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.07 (s, 2 H) 6.89-6.96 (m, 2 H) 7.22-7.28 (m, 2 H) 7.29-7.36 (m, 1 H) 7.75-7.81 (m, 1 H) 8.58 (dd, J = 4.8, 1.6 Hz, 1 H) 8.68 (d, J = 1.6 Hz, 1 H). MS ESI/APCI Dual posi: 315[M + H]⁺, 337[M + Na]⁺. MS ESI/APCI Dual nega: 313[M − H]⁻, 349[M + Cl]⁻. Reference Example A-406

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.57 (s, 3 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 5.16 (s, 2 H) 6.89-6.97 (m, 2 H) 7.07 (d, J = 7.8 Hz, 1 H) 7.20-7.25 (m, 2 H) 7.32 (d, J = 7.8 Hz, 1 H) 7.59 (t, J = 7.8 Hz, 1 H). MS ESI/APCI Dual posi: 329[M + H]⁺, 351[M + Na]⁺.

TABLE 18-59 Compound Salt No. Structure Analytical Data information Reference Example A-407

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.51 (t, J = 6.5 Hz, 2 H) 2.87 (t, J = 6.5 Hz, 2 H) 3.72 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.13 (s, 2 H) 6.89-6.97 (m, 2 H) 7.05-7.12 (m, 1 H) 7.32-7.46 (m, 4 H). MS ESI/APCI Dual posi: 332[M + H]⁺, 354[M + Na]⁺. MS ESI/APCI Dual nega: 330[M − H]⁻. Reference Example A-408

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7. 1 Hz, 2 H) 5.05 (s, 2 H) 6.89-6.95 (m, 2 H) 7.20-7.26 (m, 4 H) 7.43-7.49 (m, 2 H). MS ESI/APCI Dual posi: 398[M + H]⁺, 420[M + Na]⁺. MS ESI/APCI Dual nega: 396[M − H]⁻, 432[M + Cl]⁻. Reference Example A-409

¹H HMR (300 MHz, CHLOROFORM-d) δ ppm 1.19-1.32 (m, 6 H) 2.43-2.57 (m, 2 H) 2.66 (q, J = 7.6 Hz, 2 H) 2.79-2.96 (m, 2 H) 3.75 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 6.85 (d, J = 8.4 Hz, 1 H) 6.99-7.09 (m, 2 H) 7.17-7.25 (m, 2 H) 7.67 (dd, J = 8.4, 2.5 Hz, 1 H) 8.10 (dd, J = 2.5, 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 339[M + H]⁺. Reference Example A-410

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.96 (t, J = 7.4 Hz, 3 H) 1.19-1.32 (m, 3 H) 1.60-1.74 (m, 2 H) 2.44-2.66 (m, 4 H) 2.79-2.96 (m, 2 H) 3.75 (s, 2 H) 4.05-4.22 (m, 2 H) 6.84 (d, J = 8.4 Hz, 1 H) 6.96-7.10 (m, 2 H) 7.12-7.28 (m, 2 H) 7.67 (dd, J = 8.4, 2.5 Hz, 1 H) 8.00-8.19 (m, 1 H). MS ESI/APCI Dual posi: 343[M + H]⁺. Reference Example A-411

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22-1.30 (m, 9 H) 2.46-2.57 (m, 2 H) 2.79-2.99 (m, 3 H) 3.75 (s, 2 H) 4.08-4.20 (m, 2 H) 6.85 (d, J = 8.4 Hz, 1 H) 7.04 (d, J = 8.4 Hz, 2 H) 7.14-7.34 (m, 2 H) 7.67 (dd, J = 8.4, 2.5 Hz, 1 H) 8.11 (d, J = 2.5 Hz, 1 H). MS ESI/APCI Dual posi: 343[M + H]⁺. Reference Example A-412

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.33 (m, 3 H) 2.25 (s, 3 H) 2.47-2.59 (m, 2 H) 2.82-2.93 (m, 2 H) 3.72 (s, 2 H) 4.05-4.20 (m, 2 H) 4.33 (q, J = 8.1 Hz, 2 H) 6.74 (d, J = 8.1 Hz, 1 H) 7.04-7.18 (m, 2 H). MS EPI/APCI Dual posi: 320[M + H]⁺. Reference Example A-413

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.88 (t, J = 6.4 Hz, 2 H) 3.73 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.37 (s, 2 H) 6.78 (d, J = 8.7 Hz, 1 H) 7.30-7.41 (m, 3 H) 7.43-7.49 (m, 2 H) 7.59 (dd, J = 8.7, 2.5 Hz, 1 H) 8.08 (d, J = 2.5 Hz, 1 H). MS ESI/APCI Dual posi: 315[M + H]⁺, 337[M + Na]⁺.

TABLE 18-60 Compound Salt No. Structure Analytical Data information Reference Example A-414

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.27 (s, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.71 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.07 (s, 2 H) 6.83 (d, J = 8.2 Hz, 1 H) 7.04-7.14 (m, 2 H) 7.28-7.47 (m, 5 H). MS ESI/APCI Dual posi: 328[M + H]⁺, 350[M + Na]⁺. MS ESI/APCI Dual nega: 326[M − H]⁻. Reference Example A-415

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.48-2.55 (m, 2 H) 2.56-2.70 (m, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.07-4.23 (m, 4 H) 6.82-6.89 (m, 2 H) 7.20-7.28 (m, 2 H). MS ESI/APCI Dual posi: 320[M + H]⁺. Reference Example A-416

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.29 (m, 3 H) 2.20 (s, 3 H) 2.48-2.55 (m, 2 H) 2.56-2.72 (m, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.71 (s, 2 H) 4.08-4.23 (m, 4 H) 6.69-6.78 (m, 1 H) 7.04-7.14 (m, 2 H). MS ESI/APCI Dual posi: 334[M + H]⁺. Reference Example A-417

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.46-2.57 (m, 2 H) 2.59-2.74 (m, 2 H) 2.82-2.90 (m, 2 H) 3.73 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.25 (t, J = 6.8 Hz, 2 H) 6.86-6.96 (m, 1 H) 6.98-7.15 (m, 2 H). MS ESI/APCI Dual posi: 338[M + H]⁺. Reference Example A-418

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.37 (s, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.93 (t, J = 6.5 Hz, 2 H) 3.90 (s, 2 H) 4.14 (q, J = 7.0 Hz, 2 H) 6.98-7.07 (m, 2 H) 7.18-7.25 (m, 2 H) 7.93-8.19 (m, 1 H) 8.34 (d, J = 1.2 Hz, 1 H). MS ESI/APCI Dual posi: 316[M + H]⁺. Reference Example A-419

¹H HMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.23 (s, 6 H) 2.38-2.70 (m, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 3.77 (s, 2 H) 4.01-4.25 (m, 2 H) 6.70-6.77 (m, 1 H) 6.78-6.84 (m, 1 H) 6.87-6.99 (m, 2 H) 7.07 (d, J = 8.2 Hz, 1 H) 7.17-7.34 (m, 2 H). MS ESI/APCI Dual posi: 328[M + H]⁺. Reference Example A-420

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Kz, 3 H) 2.35 (s, 3 H) 2.51 (t, J = 6.4 Hz, 2 H) 2.86 (t, J = 6.4 Hz, 2 H) 3.71 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.08 (s, 2 H) 6.89-6.99 (m, 2 H) 7.04-7.11 (m, 1 H) 7.18 (d, J = 8.0 Hz, 2 H) 7.32 (d, J = 8.0 Hz, 2 H). MS ESI/APCI Dual posi: 346[M + H]⁺, 368[M + Na]⁺. MS ESI/APCI Dual nega: 344[M − H]⁻.

TABLE 18-61 Compound Salt No. Structure Analytical Data information Reference Example A-421

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.26 (s, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.71 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.02 (s, 2 H) 6.81 (d, J = 8.2 Hz, 1 H) 7.02- 7.14 (m, 4 H) 7.36-7.44 (m, 2 H). MS ESI/APCI Dual posi: 346[M + H]⁺, 368[M + Na]⁺. MS ESI/APCI Dual nega: 344[M − H]⁻. Reference Example A-422

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.27 (s, 3 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.71 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.06 (s, 2 H) 6.80 (d, J = 8.2 Hz, 1 H) 7.06-7.15 (m, 2 H) 7.20-7.26 (m, 2 H) 7.44-7.50 (m, 2 H). MS ESI/APCI Dual posi: 412[M + H]⁺, 434[M + Na]⁺. MS ESI/APCI Dual nega: 410[M − H]⁻, 446[M + Cl]⁻. Reference Example A-423

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.00-1.10 (m, 2 H) 1.26 (t, J = 7.2 Hz, 3 H) 1.37-1.56 (m, 3 H) 1.86-1.94 (m, 2 H) 2.14-2.23 (m, 2 H) 2.46-2.56 (m, 4 H) 2.37 (t, J = 6.4 Hz, 2 H) 4.10-4.20 (m, 3 H) 6.86-6.95 (m, 3 H) 7.22-7.29 (m, 2 H). MS ESI/APCI Dual posi: 306[M + H]⁺. Reference Example A-424

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.19-1.33 (m, 3 H) 1.34-1.71 (m, 7 H) 1.93-2.10 (m, 2 H) 2.44-2.58 (m, 4 H) 2.80-2.96 (m, 2 H) 4.04-4.23 (m, 2 H) 4.47-4.59 (m, 1 H) 6.83-6.99 (m, 3 H) 7.17-7.34 (m, 2 H). MS ESI/APCI Dual posi: 306[M + H]⁺. Reference Example A-425

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.36 (s, 3 H) 2.51 (t, J = 6.4 Hz, 2 H) 2.87 (t, J = 6.4 Hz, 2 H) 3.73 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.97-7.08 (m, 2 H) 7.14-7.25 (m, 2 H) 7.78 (d, J = 2.2 Hz, 1 H) 7.92 (d, J = 2.2 Hz, 1 H). MS ESI/APCI Dual posi: 349[M + H]⁺. Reference Example A-426

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.36 (s, 3 H) 2.52 (t, J = 6.3 Hz, 2 H) 2.87 (t, J = 6.3 Hz, 2 H) 3.76 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.99-7.09 (m, 2 H) 7.15-7.25 (m, 2 H) 7.47-7.56 (m, 1 H) 7.82 (d, J = 2.0 Hz, 1 H). MS ESI/APCI Dual posi: 333[M + H]⁺. Reference Example A427

¹H HMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.32 (s, 3 H) 2.40 (s, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.87 (t, J = 6.4 Hz, 2 H) 3.72 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.95 (s, 2 H) 7.01 (d, J = 8.4 Hz, 1 H) 7.15 (dd, J = 8.4, 2.2 Hz, 1 H) 7.34 (d, J = 2.2 Hz, 1 H). MS ESI/APCI Dual posi: 367[M + H]⁺. 389[M + Na]⁺. MS ESI/APCI Dual nega: 365[M − H]⁻.

TABLE 18-62 Compound Salt No. Structure Analytical Data information Reference Example A-428

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17-1.40 (m, 4 H) 1.58-1.92 (m, 3 H) 1.94-2.40 (m, 3 H) 2.46-2.57 (m, 2 H) 2.58-2.67 (m, 2 H) 2.83-2.96 (m, 2 H) 3.00-3.17 (m, 1 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.12-7.33 (m, 5 H). MS ESI/APCI Dual posi: 276[M + H]⁺. Reference Example A-429

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.36-0.43 (m, 2 H) 0.51-0.59 (m, 2 H) 1.19-1.29 (m, 6 H) 2.51 (t, J = 6.4 Hz, 2 H) 2.87 (t, J = 6.4 Hz, 2 H) 3.71 (s, 2 H) 4.06 (s, 2 H) 4.09-4.18 (m, 2 H) 6.75 (d, J = 8.4 Hz, 1 H) 7.57 (dd, J = 8.4, 2.5 Hz, 1 H) 8.02 (d, J = 2.5 Hz, 1 H). MS ESI/APCI Dual posi: 293[M + H]⁺. Reference Example A-430

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.06-0.16 (m, 2 H) 0.39-0.52 (m, 2 H) 0.73-0.90 (m, 1 H) 1.20-1.32 (m, 3 H) 1.61-1.71 (m, 2 H) 2.44-2.57 (m, 2 H) 2.82-2.93 (m, 2 H) 3.72 (s, 2 H) 4.06-4.20 (m, 2 H) 4.34 (t, J = 6.8 Hz, 2 H) 6.70 (d, J = 8.4 Hz, 1 H) 7.57 (dd, J = 8.4, 2.5 Hz, 1 H) 8.01-8.09 (m, 1 H). MS ESI/APCI Dual posi: 283[M + H]⁺. Reference Example A-431

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17 (t, J = 7.1 Hz, 3 H) 2.38-2.44 (m, 2 H) 2.46 (s, 3 H) 2.64-2.71 (m, 2 H) 3.60 (s, 2 H) 4.04 (q, J = 7.1 Hz, 2 H) 5.07 (s, 2 H) 6.94 (d, J = 8.7 Hz, 2 H) 7.21 (d, J = 8.7 Hz, 2 H) 7.27 (d, J = 7.9 Hz, 1 H) 7.73 (dd, J = 7.9, 2.2 Hz, 1 H) 8.51 (d, J = 2.2 Hz, 1 H). MS ESI/APCI Dual posi: 329[M + H]⁺, 351[M + Na]⁺. MS ESI/APCI Dual nega: 327[M − H]⁻. Reference Example A-432

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.73-0.81 (m, 2 H) 0.82-0.89 (m, 2 H) 1.20 (t, J = 7.1 Hz, 3 H) 2.43 (t, J = 6.7 Hz, 2 H) 2.78 (s, 2 H) 2.86 (t, J = 6.7 Hz, 2 H) 4.08 (q, J = 7.1 Hz, 2 H) 7.14-7.24 (m, 1 H) 7.25-7.38 (m, 4 H). MS ESI/APCI Dual posi: 243[M + H]⁺. Reference Example A-433

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.73-0.86 (m, 4 H) 1.21 (t, J =7.1 Hz, 3 H) 2.43 (t, J = 6.5 Hz, 2 H) 2.76 (s, 2 H) 2.85 (t, J = 6.5 Hz, 2 H) 4.09 (q, J = 7.1 Hz, 2 H) 7.19-7.33 (m, 4 H). MS ESI/APCI Dual posi: 282[M + H]⁺. Reference Example A-443

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17 (t, J = 7.1 Hz, 3 H) 2.38- 2.44 (m, 2 H) 2.64-2.72 (m, 2 H) 3.61 (s, 2 H) 4.04 (q, J = 7.1 Hz, 2 H) 5.10 (s, 2 H) 6.95-7.02 (m, 2 H) 7.20-7.27 (m, 3 H) 7.77 (dd, J = 7.7, 1.8 Hz, 1 H) 8.40 (dd, J = 4.9, 1.8 Hz, 1 H). MS ESI/APCI Dual posi: 329[M + H]⁺, 351[M + Na]⁺. MS ESI/APCI Dual nega: 327[M − H]⁻.

TABLE 18-63 Compound Salt No. Structure Analytical Data information Reference Example A-435

¹H HMR (300 MHz, CHLOROFORM-d) δ ppm 0.94-1.13 (m, 2 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.32-1.62 (m, 3 H) 1.83-1.95 (m, 2 H) 2.06-2.21 (m, 2 H) 2.43-2.57 (m, 4 H) 2.82-2.92 (m, 2 H) 3.98- 4.10 (m, 1 H) 4.10-4.20 (m, 2 H) 6.79-6.87 (m, 2 H) 6.90-6.99 (m, 2 H). MS ESI/APCI Dual posi: 324[M + H]⁺. Reference Example A-436

¹H HMR (300 MHz, CHLOROFORM-d) δ ppm 0.96-1.17 (m, 2 H) 1.27 (t, J = 7.1 Hz, 3 H) 1.37-1.67 (m, 3 H) 1.85-1.99 (m, 2 H) 2.10-2.25 (m, 2 H) 2.46-2.59 (m, 4 H) 2.88 (t, J = 6.5 Hz, 2 H) 4.05-4.30 (m, 3 H) 6.87-6.99 (m, 2 H) 7.45-7.58 (m, 2 H). MS ESI/APCI Dual pcsi: 374[M + H]⁺. Reference Example A-437

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.58-0.71 (m, 2 H) 0.90-1.02 (m, 2 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.78-1.93 (m, 1 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.80 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.75-6.83 (m, 1 H) 7.00-7.10 (m, 2 H) 7.28-7.39 (m, 3 H) 7.97-8.08 (m, 1 H). MS ESI/APCI Dual posi: 341[M + H]⁺. Reference Example A-438

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 5.17 (s, 2 H) 6.89-6.95 (m, 2 H) 7.21-7.26 (m, 2 H) 7.48 (dd, J = 8.4, 0.7 Hz, 1 H) 7.69 (dd, J = 3.4, 2.4 Hz, 1 H) 8.55 (dd, J = 2.4, 0.7 Hz, 1 H). MS ESI/APCI Dual posi: 349[M + H]⁺, 371[M + Na]⁺. MS ESI/APCI Dual nega: 347[M − H]⁻, 383[M + Cl]⁻. Reference Example A-439

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.46 (d, J = 1.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.28 (s, 2 H) 6.93-6.98 (m, 2 H) 7.21-7.26 (m, 2 H) 7.41 (q, J = 1.1 Hz, 1 H). MS ESI/APCI Dual posi: 335[M + H]⁺, 357[M + Na]⁺. MS ESI/APCI Dual nega: 333[M − H]⁻. Reference Example A-440

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.74 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.13 (s, 2 H) 6.83 (d, J = 4.5 Hz, 1 H) 6.96-7.00 (m, 2 H) 7.20-7.30 (m, 2 H) 7.39 (d, J = 4.5 Hz, 1 H) 7.51 (s, 1 H). MS ESI/APCI Dual posi: 360[M + H]⁺, 332[M + Na]⁺. MS ESI/APCI Dual nega: 358[M − H]⁻. Reference Example A-441

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.30 (m, 3 H) 2.37 (s, 3 H) 2.44-2.60 (m, 2 H) 2.88 (t, J = 6.3 Hz, 2 H) 3.76 (s, 2 H) 4.08-4.20 (m, 2 H) 7.03-7.12 (m, 2 H) 7.18-7.26 (m, 2 H) 8.49 (s, 2 H). MS ESI/APCI Dual posi: 318[M + H]⁺.

TABLE 18-64 Compound Salt No. Structure Analytical Data information Reference Example A-442

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.19 -1.32 (m, 3 H) 2.05 (s, 2 H) 2.33 (s, 3 H) 2.55 (t, J = 6.4 Hz, 2 H) 2.82-2.98 (m, 2 H) 3.67-3.79 (m, 5 H) 4.06-4.22 (m, 2 H) 7.00-7.09 (m, 2 H) 7.30-7.37 (m, 2 H) 7.56 (d, J = 1.9 Hz, 1 H) 7.89 (d, J = 1.9 Hz, 1 H). MS ESI/APCI Dual posi: 349[M + H]⁺. Reference Example A-443

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.22 (s, 3 H) 2.45-2.56 (m, 2 H) 2.83-2.94 (m, 2 H) 3.71 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.75 (q, J = 8.7 Hz, 2 H) 7.41-7.49 (m, 1 H) 7.83-7.91 (m, 1 H). MS ESI/APCI Dual posi: 321[M + H]⁺. Reference Example A-444

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.06-0.17 (m, 2 H) 0.39-0.51 (m, 2 H) 0.75-0.91 (m, 1 H) 1.18-1.30 (m, 3 H) 1.61-1.74 (m, 2 H) 2.15-2.22 (m, 3 H) 2.47-2.58 (m, 2 H) 2.81-2.94 (m, 2 H) 3.68 (s, 2 H) 4.06-4.20 (m, 2 H) 4.36 (t, J = 6.6 Hz, 2 H) 7.35-7.41 (m, 1 H) 7.80-7.90 (m, 1 H). MS ESI/APCI Dual posi: 307[M + H]⁺. Reference Example A-445

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.99-1.21 (m, 2 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.33-1.62 (m, 3 H) 1.81-1.94 (m, 2 H) 2.09-2.24 (m, 2 H) 2.42-2.60 (m, 4 H) 2.87 (t, J = 6.5 Hz, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.79-4.95 (m, 1 H) 6.56-6.70 (m, 1 H) 7.22-7.37 (m, 1 H) 7.92-8.01 (m, 1 H). MS ESI/APCI Dual posi: 325[M + H]⁺. Reference Example A-446

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (t, J = 7.1 Hz, 3 H) 1.31 (s, 6 H) 2.40 (t, J = 6.5 Hz, 2 H) 2.71 (s, 2 H) 2.80 (t, J = 6.5 Hz, 2 H) 4.07 (q, J = 7.1 Hz, 2 H) 7.24-7.34 (m, 2 H) 7.37-7.46 (m, 2H) . MS ESI/APCI Dual posi: 284[M + H]⁺. Reference Example A-447

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97-1.11 (m, 4 H) 1.26 (t, J = 7.1 Hz, 3 H) 2.01-2.16 (m, 1 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.85 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.14-7.23 (m, 1 H) 7.37-7.44 (m, 2 H) 7.47-7.55 (m, 2 H) 7.67-7.77 (m, 1 H) 8.61-8.73 (m, 1 H). MS ESI/APCI Dual posi: 324[M + H]⁺. Reference Example A-448

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.49 (s, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.90 (t, J = 6.4 Hz, 2 H) 3.81 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.06 (s, 2 H) 7.03-7.07 (m, 1 H) 7.13-7.19 (m, 1 H) 7.32-7.41 (m, 4 H) 8.24-8.27 (m, 1 H). MS ESI/APCI Dual posi: 329[M + H]⁺, 351[M + Na]⁺. MS ESI/APCI Dual nega: 327[M − H]⁻, 363[M + Cl]⁻.

TABLE 18-65 Compound Salt No. Structure Analytical Data information Reference Example A-449

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.90 (t, J = 6.5 Hz, 2 H) 3.81 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.05 (s, 2 H) 6.94-7.01 (m, 3 H) 7.27-7.42 (m, 6 H). MS ESI/APCI Dual posi: 314[M + H]⁺, 338[M + Na]⁺. MS ESI/APCI Dual nega: 312[M − H]⁻, 348[M + Cl]⁻. Reference Example A-450

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.28 (s, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.89 (t, J = 6.5 Hz, 2 H) 3.81 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.02 (s, 2 H) 6.84-6.90 (m, 2 H) 7.05-7.11 (m, 2 H) 7.30-7.41 (m, 4 H). MS ESI/APCI Dual posi: 328[M + H]⁺, 350[M + Na]⁺. MS ESI/APCI Dual nega: 326[M − H]⁻, 362[M + Cl]⁻. Reference Example A-451

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.35 (s, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.73 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.32 (s, 2 H) 6.76 (dd, J = 8.5, 0.5 Hz, 1 H) 7.18 (d, J = 8.0 Hz, 2 H) 7.35 (d, J = 8.0 Hz, 2 H) 7.58 (dd, J = 8.5, 2.4 Hz, 1 H) 8.08 (dd, J = 2.4, 0.5 Hz, 1 H). MS ESI/APCI Dual posi: 329[M + H]⁺, 351[M + Na]⁺. Reference Example A-452

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.4 Hz, 2 H) 2.88 (t, J = 6.4 Hz, 2 H) 3.73 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.33 (s, 2 H) 6.77 (dd, J = 8.5, 0.5 Hz, 1 H) 7.31-7.36 (m, 2 H) 7.36-7.42 (m, 2 H) 7.60 (dd, J = 8.5, 2.5 Hz, 1 H) 8.06 (dd, J = 2.5, 0.5 Hz, 1 H). MS ESI/APCI Dual posi: 349[M + H]⁺, 371[M + Na]⁺. MS ESI/APCI Dual nega: 347[M − H]⁻, 383[M + Cl]⁻. Reference Example A-453

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.08-0.17 (m, 2 H) 0.41-0.53 (m, 2 H) 0.76-0.93 (m, 1 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.66-1.76 (m, 2 H) 2.44-2.57 (m, 2 H) 2.77-2.94 (m, 2 H) 3.71 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.39-4.47 (m, 2 H) 7.66 (d, J = 2.2 Hz, 1 H) 7.94 (d, J = 2.2 Hz, 1 H) MS ESI/APCI Dual posi: 327[M + H]⁺. Reference Example A-454

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 8.5 Hz, 2 H) 3.86 (s, 2 H) 4.04 (s, 3 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.65-6.71 (m, 1 H) 7.30-7.36 (m, 1 H) 7.37-7.44 (m, 2 H) 7.57-7.68 (m, 1 H) 7.96-8.05 (m, 2 H). MS ESI/APCI Dual posi: 315[M + H]⁺. Reference Example A-455

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 3.87 (s, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.39-7.47 (m, 2 H) 7.63-7.77 (m, 2 H) 7.89-7.96 (m, 2 H) 8.60-8.68 (m, 1 H). MS ESI/APCI Dual posi: 319[M + H]⁺.

TABLE 18-66 Salt Compound infor- No. Structure Analytical Data mation Reference Example A-456

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.90 (t, J = 6.4 Hz, 2 H) 3.82 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.15 (s, 2 H) 7.29-7.40 (m, 5 H) 7.56-7.64 (m, 1 H) 8.43-8.48 (m, 1 H). MS ESI/APCI Dual posi: 383[M + H]⁺, 405 [M + Na]⁺. MS ESI/APCI Dual nega: 381[M − H]⁻. Reference Example A-457

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.53 (t, J = 6.5 Hz, 2 H) 2.90 (t, J = 6.5 Hz, 2 H) 3.82 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 5.41 (s, 2 H) 6.84- 6.89 (m, 1 H) 7.31-7.37 (m, 2 H) 7.39-7.45 (m, 2 H) 7.74-7.80 (m, 1 H) 8.43-8.47 (m, 1 H). MS ESI/APCI Dual posi: 383[M + H]⁺, 405 [M + Na]⁺. MS ESI/APCI Dual nega: 381[M − H]⁻. Reference Example A-458

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.92 (t, J = 6.5 Hz, 2 H) 3.83-3.87 (m, 2 H) 3.90 (s, 3 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.21-7.30 (m, 1 H) 7.37-7.45 (m, 2 H) 7.62-7.71 (m, 1 H) 7.85-7.93 (m, 2 H) 8.36-8.42 (m, 1 H). MS ESI/APCI Dual posi: 315[M + H]⁺. Reference Example A-459

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J = 7.1 Hz, 3 H) 2.63-2.76 (m, 2 H) 2.95- 3.08 (m, 2 H) 3.85 (s, 3 H) 3.98 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.19-7.54 (m, 4 H) 7.85- 7.96 (m, 2 H) 8.28-8.34 (m, 1 H). MS ESI/APCI Dual posi: 315[M + H]⁺. Reference Example A-460

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.31-1.60 (m, 5 H) 1.79-1.96 (m, 4 H) 2.47-2.57 (m, 4 H) 2.83-2.92 (m, 2 H) 3.57-3.65 (m, 1 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.45 (s, 2 H) 7.26-7.31 (m, 4 H). MS ESI/APCI Dual posi: 354[M + H]⁺. Reference Example A-461

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.94-1.15 (m, 2 H) 1.19-1.64 (m, 4 H) 1.83-1.96 (m, 2 H) 2.08-2.21 (m, 2 H) 2.44-2.57 (m, 4 H) 2.80-2.92 (m, 2 H) 4.02-4.27 (m, 4 H) 6.76-6.86 (m, 2 H) 7.16-7.24 (m, 2 H). MS ESI/APCI Dual posi: 340[M + H]⁺. Reference Example A-462

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.85-1.04 (m, 2 H) 1.20-1.58 (m, 6 H) 1.77-1.91 (m, 2 H) 2.03-2.16 (m, 2 H) 2.42-2.58 (m, 4 H) 2.86 (t, J = 6.4 Hz, 2 H) 3.20-3.35 (m, 1 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.51 (s, 2 H) 7.25-7.35 (m, 4 H). MS ESI/APCI Dual posi: 354[M + H]⁺.

TABLE 18-67 Salt Compound infor- No. Structure Analytical Data mation Reference Example A-463

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.93-1.13 (m, 2 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.32-1.59 (m, 3 H) 1.81-1.95 (m, 2 H) 2.09-2.22 (m, 2 H) 2.27 (s, 3 H) 2.44-2.56 (m, 4 H) 2.81-2.92 (m, 2 H) 4.01-4.22 (m, 3 H) 6.74-6.85 (m, 2 H) 7.01-7.11 (m, 2 H). MS ESI/APCI Dual posi: 320[M + H]⁺. Reference Example A-464

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.95-1.13 (m, 2 H) 1.15-1.31 (m, 6 H) 1.33-1.62 (m, 3 H) 1.81-1.95 (m, 2 H) 2.10-2.24 (m, 2 H) 2.44-2.65 (m, 6 H) 2.82-2.92 (m, 2 H) 4.03-4.22 (m, 3 H) 6.77-6.86 (m, 2 H) 7.05-7.13 (m, 2 H). MS ESI/APCI Dual posi: 334[M + H]⁺. Reference Example A-465

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.00-1.19 (m, 2 H) 1.27 (t, J = 7.1 Hz, 3 H) 1.32- 1.62 (m, 3 H) 1.80-1.94 (m, 2 H) 2.07-2.23 (m, 2 H) 2.42-2.60 (m, 4 H) 2.87 (t, J = 6.5 Hz, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.80-4.99 (m, 1 H) 6.57-6.68 (m, 1 H) 7.40-7.55 (m, 1 H) 8.00-8.11 (m, 1 H). MS ESI/APCI Dual posi: 341[M + H]⁺. Reference Example A-466

MS ESI/APCI Dual posi: 325[M + H]⁺. Reference Example A-467

MS ESI/APCI Dual posi: 324[M + H]⁺. Reference Example A-468

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.02-1.20 (m, 2 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.33- 1.60 (m, 3 H) 1.81-1.94 (m, 2 H) 2.10-2.27 (m, 5 H) 2.43-2.58 (m, 4 H) 2.82-2.92 (m, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.82-4.99 (m, 1 H) 6.53- 6.64 (m, 1 H) 7.30-7.41 (m, 1 H) 7.88-7.98 (m, 1 H). MS ESI/APCI Dual posi: 321[M + H]⁺. Reference Example A-469

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.54 (t, J = 6.5 Hz, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 3.86 (s, 2 H) 3.91 (s, 3 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.72- 6.80 (m, 1 H) 7.18-7.25 (m, 1 H) 7.36-7.47 (m, 2 H) 7.87-7.98 (m, 2 H) 8.46-8.55 (m, 1 H). MS ESI/APCI Dual posi: 315[M + H]⁺.

TABLE 18-68 Salt Compound infor- No. Structure Analytical Data mation Reference Example A-470

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04-1.21 (m, 2 H) 1.27 (t, J = 7.1 Hz, 3 H) 1.35- 1.62 (m, 3 H) 1.82-1.97 (m, 2 H) 2.10-2.26 (m, 2 H) 2.43-2.58 (m, 4 H) 2.82-2.93 (m, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.93-5.10 (m, 1 H) 6.70- 6.79 (m, 1 H) 7.68-7.79 (m, 1 H) 8.36-8.45 (m, 1 H). MS ESI/APCI Dual posi: 375[M + H]⁺. Reference Example A-4711

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.84-1.04 (m, 2 H) 1.20-1.54 (m, 6 H) 1.77-1.91 (m, 2 H) 2.04-2.16 (m, 2 H) 2.41-2.55 (m, 4 H) 2.81-2.89 (m, 2 H) 3.21-3.35 (m, 1 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.51 (s, 2 H) 6.96-7.07 (m, 2 H) 7.25-7.36 (m, 2 H). MS ESI/APCI Dual posi: 338[M + H]⁺. Reference Example A-472

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.02-1.21 (m, 2 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.35-1.66 (m, 3 H) 1.74-1.95 (m, 3 H) 2.11- 2.25 (m, 2 H) 2.44-2.60 (m, 4 H) 2.80-2.94 (m, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.89-5.04 (m, 1 H) 6.63-6.71 (m, 1 H) 6.76-6.86 (m, 1 H) 7.49-7.59 (m, 1 H) 8.08-8.18 (m, 1 H). MS ESI/APCI Dual posi: 307[M + H]⁺. Reference Example A-473

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22-1.29 (m, 3 H) 2.52-2.60 (m, 2 H) 2.94 (t, J = 6.5 Hz, 2 H) 3.92 (s, 2 H) 4.09-4.21 (m, 2 H) 7.10 (d, J = 9.0 Hz, 2 H) 7.38 (d, J = 9.0 Hz, 2 H) 8.07-8.11 (m, 1 H) 8.38 (d, J = 1.4 Hz, 1 H). MS ESI/APCI Dual posi: 336[M + H]⁺. Reference Example A-474

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.09-0.17 (m, 2 H) 0.46-0.54 (m, 2 H) 0.77-0.93 (m, 1 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.69 (q, J = 6.7 Hz, 2 H) 2.56 (t, J = 6.6 Hz, 2 H) 2.93 (t, J = 6.6 Hz, 2 H) 3.87 (s, 2 H) 4.06 (t, J = 6.7 Hz, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 7.14-7.19 (m, 1 H) 7.21-7.25 (m, 1 H) 8.25 (dd, J = 2.8, 0.6 Hz, 1 H). MS ESI/APCI Dual posi: 293[M + H]⁺, 315 [M + Na]⁺. Reference Example A-475

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.54-0.66 (m, 2 H) 0.84-0.93 (m, 2 H) 0.95-1.14 (m, 2 H) 1.21-1.31 (m, 3 H) 1.33-1.61 (m, 3 H) 1.78-1.95 (m, 3 H) 2.08-2.24 (m, 2 H) 2.43-2.57 (m, 4 H) 2.82-2.92 (m, 2 H) 4.01-4.22 (m, 3 H) 6.75-6.83 (m, 2 H) 6.94-7.01 (m, 2 H). MS ESI/APCI Dual posi: 346[M + H]⁺. Reference Example A-476

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.63-0.75 (m, 2 H) 0.90-1.01 (m, 2 H) 1.26 (t, J = 7.1 Hz, 3 H) 1.85-1.97 (m, 1 H) 2.49-2.59 (M, 2 H) 2.88-2.97 (m, 2 H) 3.90 (s, 2 H) 4.08- 4.21 (m, 2 H) 6.98-7.07 (m, 2 H) 7.08-7.16 (m, 2 H) 7.98-8.19 (m, 1 H) 8.34 (d, J = 1.4 Hz, 1 H). MS ESI/APCI Dual posi: 342[M + H]⁺.

TABLE 18-69 Salt Compound infor- No. Structure Analytical Data mation Reference Example A-477

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.84-1.02 (m, 2 H) 1.20-1.54 (m, 6 H) 1.78-1.89 (m, 2 H) 2.06-2.18 (m, 2 H) 2.40- 2.58 (m, 4 H) 2.81-2.89 (m, 2 H) 3.21-3.37 (m, 1 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.56 (s, 2 H) 7.24-7.37 (m, 5 H). MS ESI/APCI Dual posi: 320[M + H]⁺. Reference Example A-478

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.13-0.24 (m, 2 H) 0.43-0.59 (m, 2 H) 0.82- 1.12 (m, 3 H) 1.15-1.32 (m, 5 H) 1.34-1.53 (m, 1 H) 1.75-1.89 (m, 2 H) 1.98-2.11 (m, 2 H) 2.40-2.56 (m, 4 H) 2.81-2.90 (m, 2 H) 3.12-3.24 (m, 1 H) 3.29 (d, J = 6.8 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H). MS ESI/APCI Dual posi: 284[M + H]⁺, 306 [M + Na]⁺. Reference Example A-479

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.52-0.66 (m, 2 H) 0.85-0.98 (m, 2 H) 1.02- 1.56 (m, 8 H) 1.75-1.94 (m, 3 H) 2.09-2.25 (m, 2 H) 2.42-2.62 (m, 4 H) 2.79-2.95 (m, 2 H) 4.06-4.24 (m, 2 H) 4.82-4.99 (m, 1 H) 6.54-6.63 (m, 1 H) 7.18-7.26 (m, 1 H) 7.91- 7.98 (m, 1 H). MS ESI/APCI Dual posi: 347[M + H]⁺. Reference Example A-480

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.82-1.02 (m, 2 H) 1.12-1.31 (m, 5 H) 1.33-1.53 (m, 1 H) 1.71-1.87 (m, 2 H) 1.98- 2.10 (m, 2 H) 2.39-2.57 (m, 4 H) 2.79-2.92 (m, 4 H) 3.11-3.25 (m, 1 H) 3.66 (t, J = 7.5 Hz, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.15- 7.33 (m, 5 H). MS ESI/APCI Dual posi: 334[M + H]⁺. Reference Example A-481

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.80-1.04 (m, 2 H) 1.12-1.30 (m, 6 H) 1.35- 1.63 (m, 6 H) 1.64-1.87 (m, 4 H) 1.97-2.19 (m, 3 H) 2.40-2.56 (m, 4 H) 2.79-2.91 (m, 2 H) 3.07-3.21 (m, 1 H) 3.31 (d, J = 7.3 Hz, 2 H) 4.14 (q, J = 7.0 Hz, 2 H). MS ESI/APCI Dual posi: 312[M + H]⁺, 334 [M + Na]⁺. Reference Example A-482

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.94-1.60 (m, 11 H) 1.77-1.95 (m, 2 H) 2.07- 2.27 (m, 2 H) 2.40-2.65 (m, 6 H) 2.76-2.95 (m, 2 H) 4.15 (q, J = 7.3 Hz, 2 H) 4.81-5.04 (m, 1 H) 6.54-6.67 (m, 1 H) 7.31-7.44 (m, 1 H) 7.89-8.00 (m, 1 H). MS ESI/APCI Dual posi: 335[M + H]⁺. Reference Example A-483

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.78-1.06 (m, 2 H) 1.14-1.57 (m, 6 H) 1.74- 1.90 (m, 2 H) 2.00-2.19 (m, 2 H) 2.33 (s, 3 H) 2.40-2.56 (m, 4 H) 2.79-2.91 (m, 2 H) 3.16-3.38 (m, 1 H) 4.14 (q, J = 7.0 Hz, 2 H) 4.51 (s, 2 H) 7.08-7.28 (m, 4 H). MS ESI/APCI Dual posi: 334[M + H]⁺. Reference Example A-484

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 0.77-1.05 (m, 2 H) 1.09-2.06 (m, 15 H) 2.08- 2.29 (m, 2 H) 2.38-2.59 (m, 4 H) 2.79-2.92 (m, 2 H) 3.07-3.29 (m, 1 H) 3.92-4.24 (m, 3 H). MS ESI/APCI Dual posi: 284[M + H]⁺, 306 [M + Na]⁺. Reference Example A-485

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.86-1.06 (m, 2 H) 1.19-1.57 (m, 6 H) 1.78- 1.92 (m, 2 H) 2.04-2.21 (m, 2 H) 2.44-2.58 (m, 4 H) 2.88 (t, J = 6.4 Hz, 2 H) 3.24-3.45 (m, 1 H) 4.15 (q, J = 7.0 Hz, 2 H) 4.64 (s, 2 H) 7.44 (d, J = 8.4 Hz, 1 H) 7.66 (dd, J = 8.4, 2.3 Hz, 1 H) 8.49 (d, J = 2.3 Hz, 1 H). MS ESI/APCI Dual posi: 355[M + H]⁺.

Reference Example A-486 Ethyl N-[1-(4-chlorophenyl)-2-propanyl]-β-alaninate

To a solution of β-alanine ethyl ester hydrochloride (1.00 g) in ethanol (13.5 mL), triethylamine (907 μL), 4-chlorophenylacetone (1.32 g), acetic acid (1.5 mL) and borane-2-picoline complex (1.39 g) were added successively and the mixture was stirred at 60° C. for 30 minutes. After being cooled to room temperature, the mixture was concentrated under reduced pressure. To the resulting residue, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with chloroform twice. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-95:5) to give the titled compound as a yellow oil (1.70 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.03 (d, J=6.2 Hz, 3H) 1.22 (t, J=7.1 Hz, 3H) 2.40-2.49 (m, 2H) 2.51-2.61 (m, 1H) 2.65-2.76 (m, 1H) 2.79-2.99 (m, 3H) 4.10 (q, J=7.1 Hz, 2H) 7.06-7.15 (m, 2H) 7.21-7.29 (m, 2H).

MS ESI/APCI Dual posi: 270 [M+H]⁺.

Reference Example B-1 Ethyl N-{2-[4-(trifluoromethyl)phenyl]propan-2-yl}-β-alaninate

To a mixture of the compound (1.11 g) obtained in Reference Example 27-3, methanol (6.00 mL) and water (3.00 mL), ethyl acrylate (0.594 mL) was added and the resulting mixture was stirred at 90° C. for an hour under irradiation with microwaves. After being cooled to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with saturated brine and thereafter passed through a phase separator for concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-10:90) to give the titled compound as a pale yellow oil (957 mg). ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J=7.1 Hz, 3H) 1.47 (s, 6H) 2.39-2.49 (m, 2H) 2.53-2.61 (m, 2H) 4.14 (q, J=7.1 Hz, 2H) 7.58 (s, 4H).

MS ESI/APCI Dual posi: 304 [M+H]⁺.

In the following Reference Examples B-2 to B-19, the compounds obtained in Reference Examples 27-1 to 27-3, Reference Examples 45-1 to 47-1, or commercial grades of the corresponding amines, as well as commercial grades of the corresponding acrylic acid esters or crotonic acid esters were used as starting materials and treated by the method described in Reference Example B-1 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Tables 19-1 and 19-2.

TABLE 19-1 Compound Salt No. Structure Analytical Data information Reference Example B-2

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23 (t, J = 7.2 Hz, 3 H) 2.51 (t, J = 6.6 Hz, 2 H) 2.84 (t, J = 7.1 Hz, 2 H) 2.90-2.96 (m, 4 H) 4.12 (q, J = 7.2 Hz, 2 H) 7.26-7.30 (m, 2 H) 7.31-7.35 (m, 1 H) 7.41-7.46 (m, 2 H) 7.51-7.54 (m, 2 H) 7.56-7.60 (m, 2 H). MS ESI/APCI Dual posi: 298[M + H]⁺. Reference Example B-3

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.14-1.33 (m, 3 H) 2.34-2.56 (m, 2 H) 2.64-2.97 (m, 6 H) 4.00-4.23 (m, 2 H) 7.08-7.38 (m, 5 H). MS ESI/APCI Dual posi: 222[M + H]⁺. Reference Example B-4

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.61 (t, J = 6.4 Hz, 2 H) 3.45 (t, J = 6.4 Hz, 2 H) 4.16 (q, J = 7.1 Hz, 2 H) 6.58-6.66 (m, 2 H) 6.72 (m, 1 H) 7.13-7.22 (m, 2 H). MS ESI/APCI Dual posi: 194[M + H]⁺. Reference Example B-5

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.59 (t, J = 6.3 Hz, 2 H) 3.41 (t, J = 6.3 Hz, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 6.19-6.44 (m, 3 H) 6.93-7.18 (m, 4 H) 7.28-7.38 (m, 2 H). MS ESI/APCI Dual posi: 286[M + H]⁺. Reference Example B-6

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.62 (t, J = 6.3 Hz, 2 H) 3.44 (t, J = 6.3 Hz, 2 H) 4.17 (q, J = 7.1 Hz, 2 H) 6.59-6.65 (m, 2 H) 6.87-6.95 (m, 4 H) 6.97-7.04 (m, 1 H) 7.23-7.32 (m, 2 H). MS ESI/APCI Dual posi: 286[M + H]⁺. Reference Example B-7

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.0 Hz, 3 H) 2.55 (t, J = 6.3 Hz, 2 H) 2.97 (t, J = 6.3 Hz, 2 H) 3.99 (s, 2 H) 4.16 (q, J = 7.0 Hz, 2 H) 6.50 (t, J = 0.8 Hz, 1 H) 7.38-7.50 (m, 3 H) 7.76-7.85 (m, 2 H). MS ESI/APCI Dual posi: 275[M + H]⁺. Reference Example B-8

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.76-0.90 (m, 1 H) 0.92-1.18 (m, 6 H) 2.18- 2.33 (m, 1 H) 2.33-2.51 (m, 1 H) 2.95-3.14 (m, 1 H) 3.64 (s, 3 H) 7.43-7.54 (m, 2 H) 7.52- 7.63 (m, 2 H). MS ESI/APCI Dual posi: 302[M + H]⁺, 324[M + Na]⁺. Reference Example B-9

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.93-1.00 (m, 2 H) 1.00-1.07 (m, 2 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.46 (t, J = 6.5 Hz, 2 H) 2.85 (t, J = 6.5 Hz, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.32-7.47 (m, 5 H) 7.52-7.62 (m, 4 H). MS ESI/APCI Dual posi: 310[M + H]⁺, 332[M + Na]⁺.

Formula 19-2 Salt Compound infor- No. Structure Analytical Data mation Reference Example B-10

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.32-1.52 (m, 4 H) 1.69- 1.91 (m, 5 H) 2.48-2.56 (m, 2 H) 2.76-2.85 (m, 1 H) 2.85-2.93 (m, 2 H) 3.75 (s, 2 H) 4.14 (t, J = 7.1 Hz, 2 H) 6.93-7.06 (m, 2 H) 7.12-7.20 (m, 1 H). MS ESI/APCI Dual posi: 308[M + H]⁺, 330 [M + Na]⁺. Reference Example B-11

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.1 Hz, 3 H) 2.15-2.37 (m, 4 H) 2.41- 2.57 (m, 3 H) 2.70-2.77 (m, 2 H) 2.84-2.96 (m, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.63-4.76 (m, 1 H) 6.67-6.74 (m, 2 H) 7.16-7.24 (m, 2 H). Reference Example B-12

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.52-1.72 (m, 2 H) 1.87- 2.04 (m, 1 H) 2.32-2.45 (m, 2 H) 2.45-2.54 (m, 2 H) 2.62-2.70 (m, 2 H) 2.81-2.90 (m, 2 H) 3.80-3.98 (m, 1 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.37 (s, 2 H) 7.23-7.34 (m, 4 H). MS ESI/APCI Dual posi: 326[M + H]⁺. Reference Example B-13

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.73-1.89 (m, 2 H) 2.03- 2.24 (m, 1 H) 2.50 (t, J = 6.5 Hz, 2 H) 2.55-2.67 (m, 2 H) 2.68-2.76 (m, 2 H) 2.81-2.94 (m, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.41-4.59 (m, 1 H) 6.65-6.79 (m, 2 H) 7.13-7.25 (m, 2 H). MS ESI/APCI Dual posi: 312[M + H]⁺. Reference Example B-14

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.93-2.23 (m, 4 H) 2.28-2.56 (m, 3 H) 2.67 (d, J = 7.6 Hz, 2 H) 2.77-3.01 (m, 2 H) 4.03-4.23 (m, 3 H) 4.38 (s, 2 H) 7.21-7.35 (m, 4 H). Reference Example B-15

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J = 7.l Hz, 3 H) 2.16-2.37 (m, 7 H) 2.41- 2.61 (m, 3 H) 2.74 (d, J = 7.5 Hz, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 4.15 (q, J = 7.1 Hz, 2 H) 4.56-4.86 (m, 1 H) 6.57-6.82 (m, 2 H) 6.94-7.15 (m, 2 H). MS ESI/APCI Dual posi: 292[M + H]⁺. Reference Example B-16

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22-1.31 (m, 3 H) 2.17-2.42 (m, 4 H) 2.44- 2.60 (m, 3 H) 2.75 (d, J = 7.5 Hz, 2 H) 2.91 (t, J = 6.5 Hz, 2 H) 4.05-4.22 (m, 2 H) 4.64- 4.89 (m, 1 H) 6.83 (d, J = 8.5 Hz, 2 H) 7.51 (d, J = 8.5 Hz, 2 H). MS ESI/APCI Dual posi: 346[M + H]⁺. Reference Example B-17

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23-1.31 (m, 3 H) 2.20-2.34 (m, 4 H) 2.47-2.54 (m, 3 H) 2.74 (d, J = 7.4 Hz, 2 H) 2.90 (t, J = 6.6 Hz, 2 H) 4.15 (q, J = 7.2 Hz, 2 H) 4.68-4.73 (m, 1 H) 6.67 (dd, J = 8.3, 2.5 Hz, 1 H) 6.73-6.79 (m, 1 H) 6.88-6.93 (m, 1 H) 7.13-7.19 (m, 1 H). MS ESI/APCI Dual posi: 312[M + H]⁺. Reference Example B-18

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 1.81-1.94 (m, 2 H) 1.97-2.42 (m, 6 H) 2.53 (t, J = 6.4 Hz, 2 H) 2.90 (t, J = 6.4 Hz, 2 H) 3.80 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 7.29-7.36 (m, 2 H) 7.42- 7.47 (m, 2 H). MS ESI/APCI Dual posi: 342[M + H]⁺, 364 [M + Na]⁺. MS ESI/APCI Dual nega: 340[M − H]⁻, 376 [M + Cl]⁻. Reference Example B-19

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.02 (s, 6 H) 0.88 (s, 9 H) 1.25 (t, J = 7.1 Hz, 3 H) 2.38-2.50 (m, 2 H) 2.61-2.81 (m, 2 H) 3.40-3.51 (m, 1 H) 3.55-3.64 (m, 1 H) 3.67-3.76 (m, 1 H) 4.13 (q, J = 7.1 Hz, 2 H) 7.11 (d, J = 8.1 Hz, 2 H) 7.64 (d, J = 8.1 Hz, 2 H). MS ESI/APCI Dual posi: 478[M + H]⁺.

Reference Example C-1 Ethyl N-(5-phenylpentyl)-β-alaninate

To a solution of β-alanine ethyl hydrochloride (2.00 g) in N,N-dimethylformamide (65.0 mL), sodium hydride (60% dispersion in mineral oil, 1.15 g) was added and the mixture was stirred at room temperature for an hour. After adding (5-bromopentyl)benzene (2.52 mL), the mixture was stirred at 80° C. for 4 hours. After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was separated off and dried over anhydrous magnesium sulfate; after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-85:15) to give the titled compound as a pale yellow oil (480 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.19-1.30 (m, 3H) 1.31-1.70 (m, 6H) 2.42-2.54 (m, 2H) 2.56-2.67 (m, 4H) 2.81-2.92 (m, 2H) 4.14 (q, J=7.1 Hz, 2H) 7.10-7.22 (m, 3H) 7.23-7.32 (m, 2H).

MS ESI/APCI Dual posi: 264 [M+H]⁺.

Reference Example D-1 Ethyl 3-({[3-(4-chlorophenyl)-isoxazol-5-yl]methyl}amino)-3-methylbutanoate

(1) Synthesis of 1-(4-chlorophenyl)-N-hydroxymethaneimine

To a solution of 4-chlorobenzaldehyde (10.0 g) in chloroform (350 mL), hydroxylamine hydrochloride (10.2 g) was added and the mixture was stirred at room temperature for 18 hours in an argon atmosphere. After adding 2 mol/L hydrochloric acid (200 mL), three extractions were conducted with chloroform. The combined organic layers were washed with saturated brine and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was crystallized with a liquid mixture of n-hexane and chloroform to give 1-(4-chlorophenyl)-N-hydroxymethaneimine as a colorless solid (9.27 g). ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.34-7.39 (m, 2H) 7.48-7.54 (m, 2H) 8.10 (s, 1H).

MS ESI/APCI Dual posi: 156 [M+H]⁺.

MS ESI/APCI Dual nega: 154 [M−H]⁻.

(2) Synthesis of 5-(bromomethyl)-3-(4-chlorophenyl)-isoxazole

To a solution in chloroform (28.5 mL) of the compound (1.85 g) obtained in step (1) above, propargyl bromide (1.07 mL) and triethylamine (1.99 mL) were added and then 5% sodium hypochlorite in aqueous solution (57.0 mL) was added dropwise at 0° C. over a period of 30 minutes. The reaction mixture was brought to room temperature and stirred for 5 hours. After separating the aqueous layer, two extractions were conducted with chloroform. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-85:15) and reduced to powder with n-hexane, thus giving 5-(bromomethyl)-3-(4-chlorophenyl)-isoxazole as a colorless solid (1.01 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.51 (s, 2H) 6.58-6.64 (m, 1H) 7.38-7.52 (m, 2H) 7.68-7.79 (m, 2H).

MS ESI/APCI Dual posi: 271 [M+H]⁺.

(3) Synthesis of the Titled Compound

To a solution of ethyl 3-amino-3-methylbutyrate hydrochloride (333 mg) in tetrahydrofuran (4.00 mL), a solution in tetrahydrofuran (2.00 mL) of the compound (100 mg) obtained in step (2) above and potassium carbonate (406 mg) were added and the mixture was stirred at 60° C. for three days. After passing the reaction mixture through Celite (registered trademark), the filtrate was concentrated under reduced pressure and the resulting residue was roughly purified by preparative HPLC. To the resulting roughly purified product, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-50:50) to give the titled compound as a colorless amorphous mass.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.32 (m, 9H) 2.48 (s, 2H) 3.92 (d, J=0.9 Hz, 2H) 4.15 (q, J=7.1 Hz, 2H) 6.48 (t, J=0.9 Hz, 1H) 7.37-7.45 (m, 2H) 7.69-7.77 (m, 2H).

MS ESI posi: 337 [M+H]⁺.

MS ESI nega: 335 [M−H]⁻.

Reference Example E-1 2-(Trimethylsilyl)ethyl glycinate

(1) Synthesis of 2-(trimethylsilyl)ethyl N-[(benzyloxy)carbonyl]glycinate

To a mixture of N-[(benzyloxy)carbonyl]glycine (5.33 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.86 g), 1-hydroxybenzotriazole monohydrate (4.68 g) and chloroform (51.0 mL), 2-(trimethylsilyl)ethanol (4.36 mL) was added and the mixture was stirred at room temperature for 8 hours. To the reaction mixture, 2-(trimethylsilyl)ethanol (3.00 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.93 g) and 4-dimethylaminopyridine (312 mg) were added and the mixture was stirred at room temperature for 65 hours. After pouring the reaction mixture into a saturated aqueous solution of ammonium chloride, three extractions were conducted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-80:20) to give 2-(trimethylsilyl)ethyl N-[(benzyloxy)carbonyl]glycinate as a colorless oil (6.64 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.04 (s, 9H) 0.96-1.06 (m, 2H) 3.96 (d, J=5.6 Hz, 2H) 4.20-4.30 (m, 2H) 5.13 (s, 2H) 5.19-5.28 (m, 1H) 7.28-7.41 (m, 5H).

(2) Synthesis of the Titled Compound

To a solution in ethyl acetate (20.0 mL) of the compound (634 mg) obtained in step (1) above, 20% palladium hydroxide/carbon (63.0 mg) was added. The mixture was stirred at room temperature for an hour in a hydrogen atmosphere. After passing the reaction mixture through Celite (registered trademark), the filtrate was concentrated under reduced pressure to give the titled compound as a pale yellow oil (320 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.05 (s, 9H) 0.89-1.07 (m, 2H) 3.40 (s, 2H) 4.13-4.29 (m, 2H).

Reference Example F-1 Ethyl N-[4-(1H-benzotriazol-1-ylmethoxy)benzyl]-β-alaninate

To a mixture of 1H-benzotriazole-1-methanol (1.22 g), 4-hydroxybenzaldehyde (1.00 g), triphenylphosphine (2.26 g) and chloroform (27 mL), diisopropyl azodicarboxylate (1.9 mol/L, solution in toluene, 4.53 mL) was added under cooling with ice. After being brought to room temperature, the mixture was stirred for 2.5 hours. Following the addition of triphenylphosphine (1.13 g) and diisopropyl azodicarboxylate (1.9 mol/L, solution in toluene, 2.27 mL), the mixture was stirred for an additional 40 minutes. To the reaction mixture, methanol (165 μL) and acetic acid (750 μL) were added and the resulting mixture was stirred at the same temperature for 20 minutes. To the reaction mixture, β-alanine ethyl hydrochloride (1.38 g), triethylamine (1.26 μL) and sodium triacetoxyborohydride (2.60 g) were added and the mixture was stirred at room temperature for 1.5 hours. After adding 1 mol/L hydrochloric acid, the mixture was washed with diethyl ether. To the aqueous layer, an aqueous solution of 2 mol/L sodium hydroxide was added to provide a basic pH. Following extraction with chloroform, the combined organic layers were washed with saturated brine and thereafter passed through a phase separator for concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50) to give the titled compound as a colorless oil (1.13 g). ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (t, J=7.1 Hz, 3H) 2.47-2.52 (m, 2H) 2.81-2.87 (m, 2H) 3.71 (s, 2H) 4.12 (q, J=7.1 Hz, 2H) 6.54 (s, 2H) 6.99-7.06 (m, 2H) 7.19-7.25 (m, 2H) 7.40 (ddd, J=8.3, 7.0, 1.0 Hz, 1H) 7.53 (ddd, J=8.3, 7.0, 1.0 Hz, 1H) 7.70 (dt, J=8.3, 1.0 Hz, 1H) 8.07 (dt, J=8.3, 1.0 Hz, 1H).

MS ESI/APCI Dual posi: 355 [M+H]⁺, 377 [M+Na]⁺.

MS ESI/APCI Dual nega: 353 [M−H]⁻, 389 [M+O]⁻.

In the following Reference Examples F-2 and F-3, a commercial grade of the corresponding alcohols was used as the starting material and treated by the method descried in Reference Example F-1 or a modification thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Table 20-1.

TABLE 20-1 Salt Compound infor- No. Structure Analytical Data mation Reference Example F-2

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J = 7.1 Hz, 3 H) 2.23 (s, 3 H) 2.26-2.29 (m, 3 H) 2.51 (t, J = 6.5 Hz, 2 H) 2.87 (t, J = 6.5 Hz, 2 H) 3.73 (s, 2 H) 4.13 (q, J = 7.1 Hz, 2 H) 5.83 (s, 2 H) 5.86 (s, 1 H) 6.97-7.03 (m, 2 H) 7.19-7.26 (m, 2 H). MS ESI/APCI Dual posi: 332[M + H]⁺, 354 [M + Na]⁺. MS ESI/APCI Dual nega: 330[M − H]⁻. Reference Example F-3

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J = 7.1 Hz, 3 H) 2.52 (t, J = 6.5 Hz, 2 H) 2.88 (t, J = 6.5 Hz, 2 H) 3.75 (s, 2 H) 4.14 (q, J = 7.1 Hz, 2 H) 4.24 (s, 3 H) 5.39 (s, 2 H) 6.95-7.01 (m, 2 H) 7.12 (ddd, J = 8.4, 6.6, 0.9 Hz, 1 H) 7.24- 7.34 (m, 3 H) 7.64 (dt, J = 8.4, 1.1 Hz, 1 H) 7.69 (dt, J = 8.8, 0.9 Hz, 1 H). MS ESI/APCI Dual posi: 368[M + H]⁺, 390 [M + Na]⁺. MS ESI/APCI Dual nega: 366[M − H]⁻, 402 [M + Cl]⁻.

Reference Example G-1 3-({2-[(2-Methyl-2-propanyl)oxy]-2-oxoethyl}amino)-3-oxopropanoic acid

(1) Synthesis of benzyl 3-({2-[(2-methyl-2-propanyl)oxy]-2-oxoethyl}amino)-3-oxopropanoate

To a solution of monobenzyl malonate (2.00 g) in N,N-dimethylformamide (51.5 mL), glycine tert-butyl hydrochloride (2.07 g), triethylamine (3.13 g) and propylphosphonic acid anhydride (cyclic trimer) (48%, solution in N,N-dimethylformamide, 8.22 g) were added and the mixture was stirred at room temperature for an hour. To the reaction mixture, water was added and extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=67:33-50:50) to give benzyl 3-({2-[(2-methyl-2-propanyl)oxy]-2-oxoethyl}amino)-3-oxopropanoate as a colorless oil (1.46 g).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9H) 3.40 (s, 2H) 3.97 (d, J=5.0 Hz, 2H) 5.19 (s, 2H) 7.31-7.40 (m, 5H) 7.47-7.57 (m, 1H).

MS ESI posi: 330 [M+Na]⁺.

MS ESI nega: 306 [M−H]⁻.

(2) Synthesis of the Titled Compound

The compound (1.46 g) obtained in step (1) above was used and treated by the same technique as in Reference Example E-1(2) to give the titled compound as a colorless oil (1.03 g).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9H) 3.40 (s, 2H) 3.99 (d, J=5.0 Hz, 2H) 7.28-7.41 (m, 1H).

MS ESI posi: 240 [M+Na]⁺.

MS ESI nega: 216 [M−H]⁻.

Reference Example G-2 3-({3-[(2-Methyl-2-propanyl)oxy]-3-oxopropyl}amino)-3-oxopropanoic acid

Instead of glycine tert-butyl hydrochloride, β-alanine tert-butyl hydrochloride (1.82 g) was used and treated by the same technique as in Reference Example G-1 to give the titled compound as a colorless solid (1.03 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9H) 2.43-2.54 (m, 2H) 3.32 (s, 2H) 3.55 (q, J=6.1 Hz, 2H) 7.02-7.18 (m, 1H).

MS ESI/APCI Dual posi: 254 [M+Na]⁺.

MS ESI/APCI Dual nega: 230 [M−H]⁻.

Reference Example G-3 3-[(2-Ethoxy2-oxoethyl)amino]-3-oxopropanoic acid

To a solution of Meldrum's acid (10.0 g) in acetonitrile (231 mL), glycine ethyl hydrochloride (14.5 g) and triethylamine (14.1 g) were added and the mixture was stirred at 60° C. for 5 hours. After cooling the mixture to room temperature, ethyl acetate was added and extraction was conducted with a saturated aqueous solution of sodium hydrogencarbonate. To the combined aqueous layers, 1 mol/L hydrochloric acid was added and extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure to give the titled compound as a colorless solid (7.95 g). ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.30 (t, J=7.2 Hz, 3H) 3.44 (s, 2H) 4.10 (d, J=5.3 Hz, 2H) 4.25 (q, J=7.2 Hz, 2H).

MS ESI/APCI Dual posi: 190 [M+H]⁺.

MS ESI/APCI Dual nega: 188 [M−H]⁻.

Example 1-1 N-[(4-Hydroxy-2-oxo-1-{[4′-(trifluoromethyl)biphenyl-4-yl]methyl}-9-oxa-1-azaspiro[5.5]undec-3-en-3-yl)carbonyl]glycine

(1) Synthesis of ethyl 3-([4-(2-ethoxy-2-oxoethyl)tetrahydro-2H-pyran-4-yl]{[4′-(trifluoromethyl)biphenyl-4-yl]methyl}amino)-3-oxopropanoate

To a solution in ethyl acetate (11.6 mL) of the compound (770 mg) obtained in Reference Example A-1 and triethylamine (287 mg), ethyl malonyl chloride (341 mg) was added at 0° C. and the mixture was stirred at room temperature for 30 minutes. More of triethylamine (95.7 mg) was added and following the addition of ethyl malonyl chloride (114 mg) at 0° C., the mixture was stirred at room temperature for 30 minutes. After adding 1 mol/L hydrochloric acid, two extractions were conducted with ethyl acetate. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure to give a mixture (1.44 g) comprising ethyl 3-([4-(2-ethoxy-2-oxoethyl)tetrahydro-2H-pyran-4-yl]{[4′-(trifluoromethyl)biphenyl-4-yl]methyl}amino)-3-oxopropanoate.

MS ESI/APCI Dual posi: 522 [M+H]⁺, 544 [M+Na]⁺.

(2) Synthesis of sodium 3-(ethoxycarbonyl)-2-oxo-1-{[4′-(trifluoromethyl)biphenyl-4-yl]methyl}-9-oxa-1-azaspiro[5.5]undec-3-en-4-olate

To a solution in ethanol (24.7 mL) of the mixture (1.43 g) obtained in step (1) above, sodium ethoxide (about 20%, solution in ethanol, 1.30 mL) was added and the resulting mixture was stirred at an external temperature of 90° C. for 4 hours. After cooling the reaction mixture to room temperature, the precipitate was recovered by filtration to give sodium 3-(ethoxycarbonyl)-2-oxo-1-{[4′-(trifluoromethyl)biphenyl-4-yl]methyl}-9-oxa-1-azaspiro[5.5]undec-3-en-4-olate as a brown solid (534 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.14 (t, J=7.1 Hz, 3H) 1.40-1.55 (m, 2H) 1.74-1.92 (m, 2H) 2.42 (s, 2H) 3.37-3.46 (m, 2H) 3.61-3.71 (m, 2H) 3.94 (q, J=6.9 Hz, 2H) 4.70 (br. s., 2H) 7.40 (d, J=7.9 Hz, 2H) 7.65 (d, J=8.1 Hz, 2H) 7.75-7.82 (m, 2H) 7.84-7.92 (m, 2H).

MS ESI/APCI Dual posi: 512 [M+Na]⁺.

MS ESI/APCI Dual nega: 488 [M−H]⁻.

(3) Synthesis of tert-butyl N-[(4-hydroxy-2-oxo-1-{[4′-(trifluoromethyl)biphenyl-4-yl]methyl}-9-oxa-1-azaspiro[5.5]undec-3-en-3-yl)carbonyl]glycinate

To a solution in 1,2-dimethoxyethane (10.2 mL) of the compound (508 mg) obtained in step (2) above, triethylamine (100 mg) and glycine tert-butyl hydrochloride (200 mg) were added and the mixture was stirred at an external temperature of 90° C. for two hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=85:15-20:80) to give tert-butyl N-[(4-hydroxy-2-oxo-1-{[4′-(trifluoromethyl)biphenyl-4-yl]methyl}-9-oxa-1-azaspiro[5.5]undec-3-en-3-yl)carbonyl]glycinate as a colorless amorphous mass (329 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.47-1.53 (m, 9H) 1.59-1.68 (m, 2H) 1.99-2.16 (m, 2H) 2.83-2.98 (m. 2H) 3.44-3.60 (m, 2H) 3.79-3.93 (m, 2H) 3.99-4.08 (m, 2H) 4.84 (br. s., 2H) 7.31-7.41 (m, 2H) 7.50-7.59 (m, 2H) 7.62-7.72 (m, 4H) 10.12-10.45 (m, 1H).

MS ESI/APCI Dual posi: 575 [M+H]⁺.

MS ESI/APCI Dual nega: 573 [M−H]⁻.

(4) Synthesis of the Titled Compound

To the compound (319 mg) obtained in step (3) above, a solution (6.4 mL) of 4 mol/L hydrogen chloride in 1,4-dioxane was added and the mixture was stirred at room temperature for 18 hours. After concentrating under reduced pressure, ethyl acetate (5.00 mL) was added to the residue and with continued stirring, n-hexane (5.00 mL) was added. After stirring the reaction mixture at room temperature for 30 minutes, the precipitate was recovered by filtration to give the titled compound as a colorless solid (245 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.46-1.61 (m, 2H) 1.89-2.10 (m, 2H) 2.89-3.14 (m, 2H) 3.41-3.56 (m, 2H) 3.65-3.78 (m, 2H) 3.96-4.16 (m, 2H) 4.74-4.93 (m, 2H) 7.40-7.51 (m, 2H) 7.63-7.74 (m, 2H) 7.75-7.93 (m, 4H) 9.93-10.27 (m, 1H) 12.76-12.95 (m, 1H).

MS ESI/APCI Dual posi: 519 [M+H]⁺, 541 [M+Na]⁺.

MS ESI/APCI Dual nega: 517 [M−H]⁻.

Example 1-2 N-{[5-(Biphenyl-4-ylmethyl)-8-hydroxy-6-oxo-2-oxa-5-azaspiro[3.5]non-7-en-7-yl]carbonyl}glycine

(1) Synthesis of tert-butyl N-{[5-(biphenyl-4-ylmethyl)-8-hydroxy-6-oxo-2-oxa-5-azaspiro[3.5]non-7-en-7-yl]carbonyl}glycinate

Instead of the compound obtained in Reference Example A-1, the compound (1.90 g) obtained in Reference Example A-2 was used and treated by the same techniques as in Example 1-1(1) to (3) to give tert-butyl N-{[5-(biphenyl-4-ylmethyl)-8-hydroxy-6-oxo-2-oxa-5-azaspiro[3.5]non-7-en-7-yl]carbonyl}glycinate as a pale brown solid (2.67 g).

¹H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.43-1.52 (m, 9H) 3.01-3.23 (m, 2H) 3.94-4.11 (m, 2H) 4.37-4.62 (m, 2H) 4.74-4.93 (m, 2H) 5.06-5.21 (m, 2H) 7.24-7.50 (m, 5H) 7.51-7.62 (m, 4H) 9.95-10.57 (m, 1H).

MS ESI/APCI Dual posi: 501 [M+Na]⁺.

(2) Synthesis of the Titled Compound

To a solution in chloroform (20.0 mL) of the compound (2.60 g) obtained in step (1) above, trifluoroacetic acid (8.00 mL) was added and the mixture was stirred at room temperature for 12 hours. After concentrating under reduced pressure, ethyl acetate was added to the residue. With continued stirring, n-hexane was added and the precipitate was recovered by filtration to give the titled compound as a pale brown solid (2.18 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.08-3.28 (m, 2H) 3.93-4.12 (m, 2H) 4.45 (d, J=7.1 Hz, 2H) 4.74 (d, J=7.1 Hz, 2H) 5.01-5.18 (m, 2H) 7.26-7.52 (m, 5H) 7.57-7.71 (m, 4H) 9.80-10.34 (m, 1H) 12.89 (br. s., 1H).

MS ESI/APCI Dual posi: 423 [M+H]⁺.

Example 1-3 N-({4-Hydroxy-5-methyl-2-oxo-1-[4-(trifluoromethoxy)benzyl]-1,2,5,6-tetrahydropyridin-3-yl}carbonyl)glycine sodium salt

(1) Synthesis of tert-butyl N-({4-hydroxy-5-methyl-2-oxo-1-[4-(trifluoromethoxy)benzyl]-1,2,5,6-tetrahydropyridin-3-yl}carbonyl)glylcinate

Instead of the compound obtained in Reference Example A-1, the compound (1.12 g) obtained in Reference Example A-3 was used and treated by the same techniques as in Example 1-1(1) to (3) to give tert-butyl N-({4-hydroxy-5-methyl-2-oxo-1-[4-(trifluoromethoxy)benzyl]-1,2,5,6-tetrahydropyridin-3-yl}carbonyl)glycinate as a colorless solid (704 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04-1.16 (m, 3H) 1.42-1.56 (m, 9H) 2.61-2.76 (m, 1H) 2.93-3.07 (m, 1H) 3.26-3.38 (m, 1H) 3.97-4.04 (m, 2H) 4.50-4.68 (m, 2H) 7.11-7.33 (m, 4H) 10.13-10.57 (m, 1H).

MS ESI/APCI Dual posi: 481 [M+Na]⁺.

MS ESI/APCI Dual nega: 457 [M−H]⁻.

(2) Synthesis of N-({4-hydroxy-5-methyl-2-oxo-1-[4-(trifluoromethoxy)benzyl]-1,2,5,6-tetrahydropyridin-3-yl}carbonyl)glycine

To the compound (1.12 g) obtained in step (1) above, a solution (10.0 mL) of 4 mol/L hydrochloride in 1,4-dioxane was added and the mixture was stirred at room temperature for 16 hours. After being concentrated under reduced pressure, the reaction mixture was purified by preparative HPLC to give N-({4-hydroxy-5-methyl-2-oxo-1-[4-(trifluoromethoxy)benzyl]-1,2,5,6-tetrahydropyridin-3-yl}carbonyl)glycine as a colorless amorphous mass (482 mg).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.07-1.19 (m, 3H) 2.53-2.78 (m, 1H) 2.98-3.10 (m, 1H) 3.33-3.41 (m, 1H) 4.15-4.23 (m, 2H) 4.56-4.70 (m, 2H) 7.15-7.23 (m, 2H) 7.27-7.34 (m, 2H) 10.13-10.50 (m, 1H).

MS ESI/APCI Dual posi: 403 [M+H]⁺, 425 [M+Na]⁺.

MS ESI/APCI Dual nega: 401[M−H]⁻.

(3) Synthesis of the Titled Compound

To a solution in methanol (3.00 mL) of the compound (321 mg) obtained in step (2) above, 1 mol/L sodium hydroxide in aqueous solution (0.798 mL) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the resulting residue, isopropyl alcohol was added and thereafter the mixture was stirred overnight at room temperature. The precipitate was recovered by filtration to give the titled compound as a pale yellow solid (205 mg).

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 1.10 (d, J=7.0 Hz, 3H) 2.56-2.73 (m, 1H) 3.06 (dd, J=12.6, 7.9 Hz, 1H) 3.44 (dd, J=12.6, 5.7 Hz, 1H) 3.89 (s, 2H) 4.58 (d, J=14.9 Hz, 1H) 4.70 (d, J=14.9 Hz, 1H) 7.16-7.30 (m, 2H) 7.36-7.47 (m, 2H).

MS ESI/APCI Dual posi: 425 [M+Na]⁺.

Example 1-4 sodium N-[(1-{[6-(4-Chlorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycinate

(1) Synthesis of 2-methyl-2-propanyl N-[(1-{[6-(4-chlorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycinate

Instead of the compound obtained in Reference Example A-1, the compound (1.15 g) obtained in Reference Example A-246 was used and treated by the same techniques as in Example 1-1(1) to (3) to give 2-methyl-2-propanyl N-[(1-{[6-(4-chlorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycinate as a pale yellow gum (1.02 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.50-2.67 (m, 2H) 3.27-3.38 (m, 2H) 3.95-4.07 (m, 2H) 4.56 (s, 2H) 6.88-6.94 (m, 1H) 7.04-7.14 (m, 2H) 7.31-7.41 (m, 2H) 7.63-7.74 (m, 1H) 8.04-8.09 (m, 1H) 10.07-10.51 (m, 1H).

MS ESI/APCI Dual posi: 510 [M+Na]⁺.

MS ESI/APCI Dual nega: 486 [M−H]⁻.

(2) Synthesis of N-[(1-{[6-(4-chlorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine

To the compound (1.02 g) obtained in step (1) above, a solution (10.0 mL) of 4 mol/L hydrogen chloride in 1,4-dioxane was added and the mixture was stirred overnight at room temperature. The resulting precipitate was recovered by filtration and the solid obtained was heated upon addition of ethyl acetate. After adding acetonitrile, the mixture was cooled to room temperature and stirred at that temperature. The resulting precipitate was recovered by filtration to give a colorless solid (645 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50-2.74 (m, 2H) 3.37-3.49 (m, 2H) 3.96-4.08 (m, 2H) 4.48-4.62 (m, 2H) 7.05 (d, J=8.4 Hz, 1H) 7.14-7.20 (m, 2H) 7.42-7.49 (m, 2H) 7.79 (dd, J=8.4, 2.5 Hz, 1H) 8.07-8.14 (m, 1H) 9.94-10.26 (m, 1H) 12.87 (br. s., 1H).

MS ESI/APCI Dual posi: 432 [M+H]⁺.

MS ESI/APCI Dual nega: 430[M−H]⁻.

(3) Crystallization of N-[(1-{[6-(4-chlorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine

To the compound (30 mg) obtained in step (2) above, a liquid mixture of water and ethanol (5:4) was added and the resulting mixture was heated on a hot water bath with 80° C. until it turned to solution, which was thereafter left to stand overnight at room temperature. The solvent was distilled off under a nitrogen stream to give a colorless solid (30 mg). m.p.: 191° C.

(4) Synthesis of the Titled Compound

To a solution in acetone of the compound (645 mg) obtained in step (2) above, 1 mol/L sodium hydroxide in aqueous solution (1.50 mL) was added and the mixture was stirred at room temperature for 30 minutes. The resulting precipitate was recovered by filtration to give the titled compound as a colorless solid (543 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.53-2.59 (m, 2H) 3.34 (t, J=7.1 Hz, 2H) 3.48-3.60 (m, 2H) 4.52 (s, 2H) 7.04 (d, J=8.4 Hz, 1H) 7.12-7.21 (m, 2H) 7.36-7.50 (m, 2H) 7.79 (dd, J=8.4, 2.5 Hz, 1H) 8.09 (d, J=2.5 Hz, 1H) 10.08 (br. s., 1H).

MS ESI posi: 432 [M+H]⁺.

MS ESI nega: 430 [M−H]⁻.

In the following Examples 1-5 to 1-464, the compounds obtained in Reference Examples A-8 to A-245, A-247 to A-300, A-343 to A-486, Reference Examples B-1 to B-17, Reference Example C-1, Reference Example D-1, Reference Examples F-1 to F-3, or commercial grades of the corresponding amines were used as starting materials and treated by the methods described in Examples 1-1 to 1-4 or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Tables 21-1 to 21-67.

TABLE 21-1 Compound Salt infor- No. Structure Analytical Data mation Example 1-5

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.08-1.78 (m, 10 H) 2.74-2.90 (m, 2 H) 3.98-4.09 (m, 2 H) 4.66-4.89 (m, 2 H) 7.30-7.49 (m, 5 H) 7.55-7.68 (m, 4 H) 9.95-10.24 (m, 1 H) 12.84 (br. s., 1 H). MS ESI/APCI Dual posi: 449[M + H]⁺, 471[M + Na]⁺. MS ESI/APCI Dual nega: 447[M − H]⁻. Example 1-6

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.92-1.73 (m, 10 H) 3.31 (s, 2 H) 3.93-4.08 (m, 2 H) 4.62-4.67 (m, 2 H) 7.20- 7.44 (m, 5 H) 10.11-10.40 (m, 1 H) 12.70-12.99 (m, 1 H). MS ESI/APCI Dual posi: 373[M + H]⁺, 395[M + Na]⁺. MS ESI/APCI Dual nega: 371[M − H]⁻. Example 1-7

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.93-1.76 (m, 10 H) 3.35-3.41 (m, 2 H) 3.99-4.11 (m, 2 H) 4.70-4.85 (m, 2 H) 7.41-7.56 (m, 3 H) 7.83-7.96 (m, 4 H) 10.15-10.44 (m, 1 H) 12.75-13.01 (m, 1 H). MS ESI/APCI Dual posi: 423[M + H]⁺, 445[M + Na]⁺. MS ESI/APCI Dual nega: 421[M − H]⁻. Example 1-8

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00-1.74 (m, 10 H) 3.34-3.39 (m, 2 H) 3.96-4.09 (m, 2 H) 4.58-4.71 (m, 2 H) 7.28-7.54 (m, 5 H) 7.59-7.75 (m, 4 H) 10.13-10.42 (m, 1 H) 12.61-13.17 (M, 1 H). MS ESI/APCI Dual posi: 449[M + H]⁺, 471[M + Na]⁺. MS ESI/APCI Dual nega: 447[M − H]⁻. Example 1-9

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.48-1.94 (m, 8 H) 2.59-2.84 (m, 2 H) 3.93-4.11 (m, 2 H) 4.53-4.78 (m, 2 H) 7.29-7.51 (m, 5 H) 7.55-7.68 (m, 4 H) 9.93-10.25 (m, 1 H) 12.67-13.15 (m, 1 H). MS ESI/APCI Dual posi: 435[M + H]⁺, 457[M + Na]⁺. MS ESI/APCI Dual nega: 433[M − H]⁻. Example 1-10

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.47-1.60 (m, 2 H) 1.92-2.05 (m, 2 H) 2.86-3.12 (m, 2 H) 3.42-3.55 (m, 2 H) 3.63-3.76 (m, 2 H) 3.96-4.08 (m, 2 H) 4.69-4.90 (m, 2 H) 7.30-7.49 (m, 5 H) 7.53-7.70 (m, 4 H) 9.95-10.26 (m, 1 H). MS ESI/APCI Dual posi: 451[M + H]⁺. MS ESI/APCI Dual nega: 449[M − H]⁻.

TABLE 21-2 Compound Salt No. Structure Analytical Data information Example 1-11

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.19-1.40 (m, 2 H) 1.72-1.89 (m, 2 H) 3.29-3.38 (m, 2 H) 3.43-3.51 (m, 2 H) 3.56-3.65 (m, 2 H) 3.97-4.07 (m, 2 H) 4.58-4.75 (m, 2 H) 7.32-7.50 (m, 5 H) 7.62-7.70 (m, 4 H) 10.14-10.33 (m, 1 H). MS ESI/APCI Dual posi: 451[M + H]⁺, 473[M + Na]⁺. MS ESI/APCI Dual nega: 449[M − H]⁻. Example 1-12

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.58-1.95 (m, 4 H) 2.28-2.47 (m, 2 H) 2.76-3.08 (m, 2 H) 3.95-4.12 (m, 2 H) 4.78-5.03 (m, 2 H) 7.29-7.51 (m, 5 H) 7.57-7.68 (m, 4 H) 9.87-10.29 (m, 1 H) 12.69-13.02 (m, 1 H). MS ESI/APCI Dual posi: 421[M + H]⁺. Example 1-13

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.23-1.94 (m, 8 H) 3.15-3.28 (m, 2 H) 3.97-4.09 (m, 2 H) 4.56-4.71 (m, 2 H) 7.29-7.53 (m, 5 H) 7.60-7.74 (m, 4 H) 10.13-10.41 (m, 1 H). MS ESI/APCI Dual posi: 435[M + H]⁺, 457[M + Na]⁺. Example 1-14

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.12-1.60 (m, 10 H) 1.62-1.82 (m, 2 H) 3.11-3.24 (m, 2 H) 3.96-4.07 (m, 2 H) 4.54-4.73 (m, 2 H) 7.30-7.52 (m, 5 H) 7.58-7.73 (m, 4 H) 10.12-10.42 (m, 1 H). MS ESI/APCI Dual posi: 463[M + H]⁺, 485[M + Na]⁺. MS ESI/APCI Dual nega: 461[M − H]⁻. Example 1-15

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.50-2.02 (m, 4 H) 2.12- 2.41 (m, 2 H) 3.49 (s, 2 H) 3.93-4.17 (m, 2 H) 4.56- 4.78 (m, 2 H) 7.28-7.54 (m, 5 H) 7.57-7.74 (m, 4 H) 10.00- 10.44 (m, 1 H) 12.77-13.03 (m, 1 H). MS ESI/APCI Dual posi: 421[M + H]⁺, 443[M + Na]⁺. MS ESI/APCI Dual nega: 419[M − H]⁻. Example 1-16

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.64-2.73 (m, 2 H) 3.36- 3.49 (m, 2 H) 3.97-4.10 (m, 2 H) 4.55-4.71 (m, 2 H) 7.26- 7.51 (m, 5 H) 7.59-7.70 (m, 4 H) 10.01-10.30 (m, 1 H) 12.67-13.04 (m, 1 H). MS ESI/APCI Dual posi: 381[M + H]⁺, 403[M + Na]⁺. MS ESI/APCI Dual nega: 379[M − H]⁻. Example 1-17

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.24 (s, 6 H) 3.16 (s, 2 H) 3.91-4.14 (m, 2 H) 4.59-4.81 (m, 2 H) 7.27-7.49 (m, 5 H) 7.56-7.67 (m, 4 H) 9.96-10.27 (m, 1 H). MS ESI/APCI Dual posi: 409[M + H]⁺, 431[M + Na]⁺. MS ESI/APCI Dual nega: 407[M − H]⁻.

TABLE 21-3 Compound Salt infor- No. Structure Analytical Data mation Example 1-18

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.47-2.73 (m, 2 H) 3.24-3.41 (m, 2 H) 4.12-4.27 (m, 2 H) 4.52-4.65 (m, 2 H) 7.17-7.25 (m, 2 H) 7.28-7.36 (m, 2 H) 10.07-10.50 (m, 1 H). MS ESI/APCI Dual posi: 339[M + H]⁺, 361[M + Na]⁺. MS ESI/APCI Dual nega: 337[M − H]. Example 1-19

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.57-2.70 (m, 2 H) 3.31-3.42 (m, 2 H) 4.17-4.23 (m, 2 H) 4.59-4.74 (m, 2 H) 7.32-7.47 (m, 2 H) 7.53-7.70 (m, 2 H) 10.06-10.48 (m, 1 H) . MS ESI/APCI Dual posi: 373[M + H]⁺, 395[M + Na]⁺. MS ESI/APCI Dual nega: 371[M − H]⁻. Example 1-20

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.16 (d, J = 6.6 Hz, 3 H) 2.15-2.38 (m, 1 H) 3.02- 3.14 (m, 1 H) 3.61-3.77 (m, 1 H) 3.95-4.07 (m, 2 H) 4.13-4.38 (m, 1 H) 4.96-5.10 (m, 1 H) 7.32-7.49 (m, 5 H) 7.58-7.68 (m, 4 H) 9.91- 10.24 (m, 1 H). MS ESI/APCI Dual posi: 395[M + H]⁺, 417[M + Na]⁺. MS ESI/APCI Dual nega: 393[M − H]⁻. Example 1-21

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.45-2.71 (m, 2 H) 3.20-3.47 (m, 2 H) 4.17-4.22 (m, 2 H) 4.64 (s, 2 H) 7.13-7.48 (m, 5 H) 10.15- 10.47 (m, 1 H). MS ESI/APCI Dual posi: 305[M + H]⁺, 327[M + Na]⁺. MS ESI/APCI Dual nega: 303[M − H]⁻. Example 1-22

¹H HMR (600 MHz, DMSO-d₆) δ ppm 1.09 (d, J = 7.0 Hz, 3 H) 2.78-2.90 (m, 1 H) 3.05-3.20 (m, 1 H) 3.43-3.56 (m, 1 H) 3.98-4.09 (m, 2 H) 4.51-4.80 (m, 2 H) 7.32-7.50 (m, 5 H) 7.59-7.70 (m, 4 H) 9.99-10.38 (m, 1 H). MS ESI/APCI Dual posi: 395[M + H]⁺, 417[M + Na]⁺. MS ESI/APCI Dual nega: 393[M − H]⁻. Example 1-23

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.60-2.67 (m, 2 H) 3.29-3.37 (m, 2 H) 4.16-4.23 (m, 2 H) 4.54-4.60 (m, 2 H) 7.12-7.19 (m, 2 H) 7.43-7.52 (m, 2 H) 10.12-10.50 (m, 1 H). MS ESI/APCI Dual posi: 383[M + H]⁺, 405[M + Na]⁺. MS ESI/APCI Dual nega: 381[M − H]⁻. Example 1-24

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.42-2.77 (m, 2 H) 3.23-3.51 (m, 2 H) 3.93-4.14 (m, 2 H) 4.58-4.84 (m, 2 H) 7.23- 7.33 (m, 1 H) 7.33-7.51 (m, 4 H) 7.52-7.60 (m, 2 H) 7.61-7.69 (m, 2 H) 9.90-10.31 (m, 1 H) 12.85 (br. s., 1 H). MS ESI/APCI Dual posi: 381[M + H]⁺. MS ESI/APCI Dual nega: 379[M − H]⁻.

TABLE 21-4 Compound Salt No. Structure Analytical Data information Example 1-25

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.63-2.78 (m, 2 H) 3.36- 3.53 (m, 2 H) 3.93-4.09 (m, 2 H) 4.58-4.76 (m, 2 H) 7.21- 7.74 (m, 9 H) 9.96-10.31 (m, 1 H) 12.67-12.98 (m, 1 H). MS ESI/APCI Dual posi: 381[M + H]⁺, 403[M + Na]⁺. MS ESI/APCI Dual nega: 379[M − H]⁻. Example 1-26

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.97-1.24 (m, 2 H) 1.31- 1.56 (m, 2 H) 1.63-1.93 (m, 5 H) 2.41-3.36 (m, 5 H) 3.37- 3.54 (m, 2 H) 3.94-4.08 (m, 2 H) 7.09-7.35 (m, 5 H) 10.02-10.21 (m, 1 H) 12.67-12.96 (m, 1 H). MS ESI/APCI Dual posi: 387[M + H]⁺, 409[M + Na]⁺. MS ESI/APCI Dual nega: 385[M − H]⁻. Example 1-27

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.94-1.10 (m, 6 H) 3.17- 3.24 (m, 2 H) 3.98-4.06 (m, 2 H) 4.59-4.70 (m, 2 H) 7.31- 7.48 (m, 5 H) 7.59-7.69 (m, 4 H) 10.09-10.37 (m, 1 H). MS ESI/APCI Dual posi: 409[M + H]⁺, 431[M + Na]⁺. MS ESI/APCI Dual nega: 407[M − H]⁻. Example 1-28

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.44-2.71 (m, 2 H) 3.34- 3.45 (m, 2 H) 3.97-4.07 (m, 2 H) 4.49-4.64 (m, 2 H) 6.93- 7.04 (m, 4 H) 7.09-7.17 (m, 1 H) 7.25-7.42 (m, 4 H) 9.96-10.27 (m, 1 H) 12.65-12.98 (m, 1 H). MS ESI/APCI Dual posi: 397[M + H]⁺, 419[M + Na]⁺. MS ESI/APCI Dual nega: 395[M − H]⁻. Example 1-29

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.51-2.75 (m, 2 H) 3.37- 3.48 (m, 2 H) 3.95-4.12 (m, 2 H) 4.64-4.85 (m, 2 H) 7.40- 7.45 (m, 1 H) 7.47-7.54 (m, 2 H) 7.81 (s, 1 H) 7.86- 7.96 (m, 3 H) 10.02-10.31 (m, 1 H). MS ESI/APCI Dual posi: 355[M + H]⁺, 377[M + Na]⁺. MS ESI/APCI Dual nega: 353[M − H]⁻. Example 1-30

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23-1.46 (m, 2 H) 1.49-1.86 (m, 4 H) 2.42-2.73 (m, 4 H) 3.24-3.54 (m, 4 H) 4.08-4.22 (m, 2 H) 7.13-7.22 (m, 3 H) 7.23-7.31 (m, 2 H) 10.11-10.43 (m, 1 H). MS ESI/APCI Dual posi: 361[M + H]⁺, 383[M + Na]⁺. MS ESI/APCI Dual nega: 359[M − H]⁻. Example 1-31

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.56-2.64 (m, 2 H) 2.79- 2.92 (m, 2 H) 3.36-3.47 (m, 2 H) 3.53-3.69 (m, 2 H) 3.96- 4.06 (m, 2 H) 7.31-7.38 (m, 3 H) 7.42-7.48 (m, 2 H) 7.58-7.63 (m, 2 H) 7.64-7.67 (m, 2 H) 9.97-10.20 (m, 1 H). MS ESI/APCI Dual posi: 395[M + H]⁺, 417[M + Na]⁺. MS ESI/APCI Dual nega: 393[M − H]⁻.

TABLE 21-5 Compound Salt No. Structure Analytical Data information Example 1-32

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.79 (t, J = 6.8 Hz, 2 H) 3.52 (t, J = 7.0 Hz, 2 H) 3.96-4.12 (m, 2 H) 4.82-4.97 (m, 2 H) 7.80 (d, J = 8.7 Hz, 1 H) 7.89-7.99 (m, 1 H) 8.14 (s, 1 H) 8.26 (d, J = 8.7 Hz, 1 H) 8.91-9.03 (m, 1 H) 9.20 (d, J = 4.5 Hz, 1 H) 9.98 (br. s., 1 H). MS ESI/APCI Dual posi: 356[M + H]⁺. MS ESI/APCI Dual nega: 354[M − H]⁻. HCl Example 1-33

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.42-2.65 (m, 2 H) 3.34- 3.45 (m, 2 H) 4.00-4.10 (m, 2 H) 5.00-5.13 (m, 2 H) 7.39- 7.64 (m, 4 H) 7.84-7.92 (m, 1 H) 7.94-8.01 (m, 1 H) 8.07-8.16 (m, 1 H) 9.99-10.34 (m, 1 H) 12.65-13.04 (m, 1 H). MS ESI/APCI Dual posi: 355[M + H]⁺, 377[M + Na]⁺. MS ESI/APCI Dual nega: 353[M − H]⁻. Example 1-34

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.36-2.56 (m, 2 H) 2.79-2.94 (m, 2 H) 3.12-3.26 (m, 2 H) 3.55-3.70 (m, 2 H) 4.04-4.20 (m, 2 H) 7.15-7.36 (m, 5 H) 10.01-10.39 (m, 1 H). MS ESI/APCI Dual posi: 341[M + Na]⁺. MS ESI/APCI Dual nega: 317[M − H]⁻. Example 1-35

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.53-2.82 (m, 2 H) 3.44 (t, J = 6.8 Hz, 2 H) 3.93-4.12 (m, 2 H) 4.67 (s, 2 H) 7.49 (d, J = 8.4 Hz, 2 H) 7.61-7.70 (m, 1 H) 8.07 (d, J = 8.4 Hz, 2 H) 8.13-8.29 (m, 2 H) 8.77 (d, J = 4.7 Hz, 1 H) 9.90-10.27 (m, 1 H). MS ESI/APCI Dual posi: 382[M + H]⁺, 404[M + Na]⁺. MS ESI/APCI Dual nega: 380[M − H]⁻. HCl Example 1-36

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 9 H) 2.53-2.71 (m, 2 H) 3.33-3.44 (m, 2 H) 4.17-4.24 (m, 2 H) 4.63- 4.70 (m, 2 H) 7.29-7.37 (m, 2 H) 7.42-7.61 (m, 6 H) 10.20-10.46 (m, 1 H). MS ESI/APCI Dual posi: 437[M + H]⁺, 459[M + Na]⁺. MS ESI/APCI Dual nega: 435[M − H]⁻. Example 1-37

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18-1.51 (m, 5 H) 1.68-1.96 (m, 5 H) 2.41-2.68 (m, 3 H) 3.29-3.41 (m, 2 H) 4.14-4.23 (m, 2 H) 4.56-4.62 (m, 2 H) 7.14-7.21 (m, 4 H) 10.21-10.43 (m, 1 H). MS ESI/APCI Dual posi: 387[M + H]⁺, 409[M + Na]⁺. MS ESI/APCI Dual nega: 385[M − H]⁻. Example 1-38

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.59-2.91 (m, 2 H) 3.72-3.89 (m, 2 H) 3.97-4.10 (m, 2 H) 7.17-7.52 (m, 5 H) 9.80-10.39 (m, 1 H) 12.57-13.07 (m, 1 H). MS ESI/APCI Dual posi: 291[M + H]⁺, 313[M + Na]⁺. MS ESI/APCI Dual nega: 289[M − H]⁻.

TABLE 21-6 Compound Salt No. Structure Analytical Data information Example 1-39

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.56-2.87 (m, 2 H) 3.76-3.88 (m, 2 H) 3.96-4.09 (m, 2 H) 6.82-6.95 (m, 1 H) 6.97-7.21 (m, 5 H) 7.34-7.47 (m, 3 H) 9.77-10.40 (m, 1 H) 12.73-12.98 (m, 1 H). MS ESI/APCI Dual posi: 383[M + H]⁺, 405[M + Na]^(+.) MS ESI/APCI Dual nega: 381[M − H]⁻. Example 1-40

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.60-2.90 (m, 2 H) 3.72-3.87 (m, 2 H) 3.94-4.12 (m, 2 H) 6.97-7.23 (m, 5 H) 7.25-7.50 (m, 4 H) 9.83-10.38 (m, 1 H) 12.72-13.05 (m, 1 H). MS ESI/APCI Dual posi: 383[M + H]⁺, 405[M + Na]⁺. MS ESI/APCI Dual nega: 381[M − H]⁻. Example 1-41

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.67-2.82 (m, 2 H) 3.46-3.61 (m, 2 H) 3.96-4.07 (m, 2 H) 4.62 (s, 2 H) 7.28-7.71 (m, 3 H) 8.24-8.55 (m, 2 H) 8.86 (s, 2 H) 9.78-10.08 (m, 1 H). MS ESI/APCI Dual posi: 383[M + H]⁺, 405[M + Na]⁺. Example 1-42

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.50-2.67 (m, 2 H) 3.25-3.39 (m, 2 H) 3.96 (s, 2 H) 4.15-4.22 (m, 2 H) 4.50-4.63 (m, 2 H) 7.12-7.33 (m, 9 H) 10.11-10.50 (m, 1 H). MS ESI/APCI Dual posi: 395[M + H]⁺, 417[M + Na]⁺. MS ESI/APCI Dual nega: 393[M − H]⁻. Example 1-43

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17-2.00 (m, 10 H) 2.61-2.92 (m, 3 H) 3.50 (t, J = 7.2 Hz, 2 H) 4.01 (d, J = 5.4 Hz, 2 H) 4.55 (s, 2 H) 8.71 (s, 2 H) 9.93 (br. s., 1 H). MS ESI/APCI Dual posi: 389[M + H]⁺, 411[M + Na]⁺. MS ESI/APCI Dual nega: 387[M − H]⁻. HCl Example 1-44

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.67-2.77 (m, 2 H) 3.41-3.52 (m, 2 H) 3.96-4.11 (m, 2 H) 4.72-4.91 (m, 2 H) 7.33-7.57 (m, 3 H) 7.79-7.98 (m, 3 H) 9.87-10.05 (m, 1 H). MS ESI/APCI Dual posi: 388[M + H]⁺. MS ESI/APCI Dual nega: 386[M − H]⁻. HCl Example 1-45

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.74 (t, J = 7.3 Hz, 2 H) 3.58 (t, J = 7.3 Hz, 2 H) 4.15-4.23 (m, 2 H) 4.70-4.80 (m, 2 H) 6.52-6.57 (m, 1 H) 7.41- 7.51 (m, 3 H) 7.74-7.83 (m, 2 H) 9.97-10.52 (m, 1 H). MS ESI/APCI Dual posi: 372[M + H]⁺, 394[M + Na]⁺. MS ESI/APCI Dual nega: 370[M − H]⁻.

TABLE 21-7 Compound Salt No. Structure Analytical Data information Example 1-46

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.67-1.76 (m, 4 H) 2.56- 2.75 (m, 6 H) 3.25-3.40 (m, 2 H) 3.97-4.07 (m, 2 H) 4.44- 4.55 (m, 2 H) 6.90-7.11 (m, 3 H) 9.98-10.27 (m, 1 H). MS ESI/APCI Dual posi: 359[M + H]⁺, 381[M + Na]⁺. MS ESI/APCI Dual nega: 357[M − H]⁻. Example 1-47

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.28 (s, 3 H) 2.48-2.69 (m, 2 H) 3.06-3.61 (m, 2 H) 3.88-4.14 (m, 2 H) 4.36- 4.73 (m, 2 H) 7.12-7.28 (m, 4 H) 9.79-10.41 (m, 1 H) 12.81 (br. s, 1 H). MS ESI/APCI Dual posi: 319[M + H]⁺, 341[M + Na]⁺. MS ESI/APCI Dual nega: 317[M − H]⁻. Example 1-48

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.43-2.64 (m, 2 H) 3.25- 3.42 (m, 2 H) 3.73 (s, 3 H) 3.94-4.08 (m, 2 H) 4.44-4.58 (m, 2 H) 6.75-7.04 (m, 2 H) 7.08-7.40 (m, 2 H) 9.94- 10.31 (m, 1 H) 12.86 (br. s, 1 H). MS ESI/APCI Dual posi: 335[M + H]⁺, 357[M + Na]⁺. MS ESI/APCI Dual nega: 333[M − H]⁻. Example 1-49

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.61-2.70 (m, 1 H) 3.01-3.24 (m, 1 H) 3.51-3.73 (m, 1 H) 4.11-4.31 (m, 2 H) 4.53-4.59 (m, 1 H) 5.44-5.63 (m, 1 H) 7.11-7.17 (m, 2 H) 7.19-7.24 (m, 2 H) 7.26-7.39 (m, 6 H) 10.24-10.39 (m, 1 H). MS ESI/APCI Dual posi: 381[M + H]⁺, 403[M + Na]⁺. MS ESI/APCI Dual nega: 379[M − H]⁻. Example 1-50

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.64-2.71 (m, 1 H) 3.05-3.28 (m, 1 H) 3.59-3.79 (m, 1 H) 4.13-4.32 (m, 2 H) 4.59-4.64 (m, 1 H) 5.47-5.67 (m, 1 H) 7.13-7.20 (m, 2 H) 7.27-7.40 (m, 5 H) 7.41-7.47 (m, 2 H) 7.53-7.60 (m, 4 H) 10.28-10.42 (m, 1 H). MS ESI/APCI Dual posi: 457[M + H]⁺, 479[M + Na]⁺. MS ESI/APCI Dual nega: 455[M − H]⁻. Example 1-51

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07-1.43 (m, 3 H) 1.44-1.66 (m, 2 H) 1.68-1.88 (m, 2 H) 2.35-2.65 (m, 1 H) 2.76-3.09 (m, 1 H) 3.25-3.45 (m, 1 H) 3.89-4.32 (m, 3 H) 5.22-5.44 (m, 1 H) 7.29-7.49 (m, 5 H) 7.51-7.62 (m, 4 H) 10.21-10.57 (m, 1 H). MS ESI/APCI Dual posi: 435[M + H]⁺, 457[M + Na]⁺. MS ESI/APCI Dual nega: 433[M − H]⁻. Example 1-52

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.92-1.46 (m, 4 H) 1.60- 1.81 (m, 2 H) 2.05-2.78 (m, 3 H) 3.22-3.39 (m, 1 H) 3.98- 4.12 (m, 2 H) 4.45-4.69 (m, 1 H) 4.93-5.11 (m, 1 H) 7.24-7.51 (m, 5 H) 7.58-7.70 (m, 4 H) 10.09-10.42 (m, 1 H) 12.74-12.98 (m, 1 H). MS ESI/APCI Dual posi: 457[M + Na]⁺. MS ESI/APCI Dual nega: 433[M − H]⁻.

TABLE 21-8 Compound Salt infor- No. Structure Analytical Data mation Example 1-53

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (t, J = 7.5 Hz, 3 H) 2.50-2.72 (m, 4 H) 3.27-3.40 (m, 2 H) 4.13-4.22 (m, 2 H) 4.55-4.63 (m, 2 H) 7.15-7.21 (m, 4 H) 10.14- 10.46 (m, 1 H). MS ESI/APCI Dual posi: 333[M + H]⁺, 355[M + Na]⁺. MS ESI/APCI Dual nega: 331[M − H]⁻. Example 1-54

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.59-2.76 (m, 2 H) 3.34-3.45 (m, 2 H) 4.15-4.25 (m, 2 H) 4.83-4.93 (m, 2 H) 7.55 (d, J = 8.2 Hz, 1 H) 7.76-7.86 (m, 1 H) 7.93 (s, 1 H) 9.91-10.67 (m, 1 H). MS ESI/APCI Dual posi: 441[M + H]⁺, 463[M + Na]⁺. MS ESI/APCI Dual nega: 439[M − H]⁻. Example 1-55

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29-1.33 (m, 9 H) 2.52-2.67 (m, 2 H) 3.30-3.41 (m, 2 H) 4.15-4.23 (m, 2 H) 4.56-4.63 (m, 2 H) 7.19 (d, J = 8.5 Hz, 2 H) 7.32- 7.40 (m, 2 H) 10.21-10.43 (m, 1 H). MS ESI/APCI Dual posi: 361[M + H]⁺, 383[M + Na]⁺. MS ESI/APCI Dual nega: 359[M − H]⁻. Example 1-56

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.65-2.74 (m, 2 H) 3.29-3.43 (m, 2 H) 4.13-4.26 (m, 2 H) 4.77-4.90 (m, 2 H) 7.34-7.45 (m, 2 H) 7.55 (t, J = 7.5 Hz, 1 H) 7.61- 7.76 (m, 1 H) 10.13-10.51 (m, 1 H). MS ESI/APCI Dual posi: 373[M + H]⁺, 395[M + Na]⁺. MS ESI/APCI Dual nega: 371[M − H]⁻. Example 1-57

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.36-3.88 (m, 3 H) 4.09-4.33 (m, 2 H) 4.54-4.71 (m, 2 H) 7.08-7.60 (m, 14 H) 10.29-10.56 (m, 1 H). MS ESI/APCI Dual posi: 457[M + H]⁺, 479[M + Na]⁺. MS ESI/APCI Dual nega: 455[M − H]⁻. Example 1-58

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54-2.70 (m, 2 H) 3.28-3.43 (m, 2 H) 4.13-4.24 (m, 2 H) 4.60-4.71 (m, 2 H) 7.42-7.64 (m, 4 H) 10.09-10.53 (m, 1 H). MS ESI/APCI Dual posi: 373[M + H]⁺, 395[M + Na]⁺. MS ESI/APCI Dual nega: 371[M − H]⁻. Example 1-59

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.57-2.75 (m, 2 H) 3.33-3.46 (m, 2 H) 4.15-4.27 (m, 2 H) 4.67-4.77 (m, 2 H) 7.73 (s, 2 H) 7.79-7.86 (m, 1 H) 10.00-10.65 (m, 1 H). MS ESI/APCI Dual posi: 441[M + H]⁺, 463[M + Na]⁺. MS ESI/APCI Dual nega: 439[M − H]⁻.

TABLE 21-9 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-60

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.21- 2.35 (m, 6 H) 2.45-2.70 (m, 2 H) 3.17-3.38 (m, 2 H) 4.05-4.29 (m, 2 H) 4.47-4.74 (m, 2 H) 6.84-7.12 (m, 3 H) 10.16-10.49 (m, 1 H). MS ESI/APCI Dual posi: 333[M + H]⁺, 355[M + Na]⁺. MS ESI/APCI Dual nega: 331[M − H]⁻. Example 1-61

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.51- 2.68 (m, 2 H) 3.28-3.41 (m, 2 H) 3.74-3.86 (m, 3 H) 4.09-4.28 (m, 2 H) 4.59 (s, 2 H) 6.77-6.89 (m, 3 H) 7.20-7.32 (m, 1 H) 10.11-10.49 (m, 1 H). MS ESI/APCI Dual posi: 335[M + H]⁺, 357[M + Na]⁺. MS ESI/APCI Dual nega: 333[M − H]⁻. Example 1-62

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.19- 2.35 (m, 3 H) 2.44-2.66 (m, 2 H) 3.13-3.37 (m, 2 H) 3.60-3.94 (m, 3 H) 4.12-4.28 (m, 2 H) 4.50-4.63 (m, 2 H) 6.65-6.81 (m, 2 H) 7.00-7.13 (m, 1 H) 10.14- 10.47 (m, 1 H). MS ESI/APCI Dual posi: 349[M + H]⁺, 371[M + Na]⁺. MS ESI/APCI Dual nega: 347[M − H]⁻. Example 1-63

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.02-1.73 (m, 10 H) 2.70-2.96 (m, 2 H) 3.94-4.07 (m, 2 H) 4.73- 4.91 (m, 2 H) 7.45-7.56 (m, 2 H) 7.61-7.70 (m, 2 H) 9.91-10.22 (m, 1 H) 12.76-12.93 (m, 1 H). MS ESI/APCI Dual posi: 441[M + H]⁺, 463[M + Na]⁺. MS ESI/APCI Dual nega: 439[M − H]⁻. Example 1-64

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.16-1.38 (m, 2 H) 1.71-1.90 (m, 2 H) 3.33-3.41 (m, 2 H) 3.44-3.52 (m, 2 H) 3.58-3.65 (m, 2 H) 3.99-4.09 (m, 2 H) 4.66- 4.76 (m, 2 H) 7.50-7.61 (m, 2 H) 7.66-7.76 (m, 2 H) 10.08-10.35 (m, 1 H) 12.71-13.00 (m, 1 H). MS ESI/APCI Dual posi: 443[M + H]⁺, 465[M + Na]⁺. MS ESI/APCI Dual nega: 441[M − H]⁻. Example 1-65

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.46 (s, 3 H) 2.59-2.69 (m, 2 H) 3.32-3.40 (m, 2 H) 3.95-4.05 (m, 2 H) 4.42-4.64 (m, 2 H) 7.16-7.29 (m, 4 H) 10.00- 10.24 (m, 1 H) 12.87 (br. s., 1 H). MS ESI/APCI Dual posi: 351[M + H]⁺, 373[M + Na]⁺. MS ESI/APCI Dual nega: 349[M − H]⁻. Example 1-66

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.53- 2.72 (m, 2 H) 3.28-3.43 (m, 2 H) 4.11-4.26 (m, 2 H) 4.51- 4.67 (m, 2 H) 7.12-7.19 (m, 1 H) 7.20-7.36 (m, 3 H) 10.07-10.50 (m, 1 H). MS ESI/APCI Dual posi: 339[M + H]⁺, 361[M + Na]⁺. MS ESI/APCI Dual nega: 337[M − H]⁻.

TABLE 21-10 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-67

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.50- 2.73 (m, 2 H) 3.26-3.42 (m, 2 H) 4.07-4.28 (m, 2 H) 4.47-4.64 (m, 2 H) 7.03-7.17 (m, 1 H) 7.30-7.53 (m, 2 H) 10.03-10.53 (m, 1 H). MS ESI/APCI Dual posi: 373[M + H]⁺, 395[M + Na]⁺. MS ESI/APCI Dual nega: 371[M − H]⁻. Example 1-68

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.51- 2.77 (m, 2 H) 3.22-3.48 (m, 2 H) 4.09-4.27 (m, 2 H) 4.63 (s, 2 H) 7.08-7.24 (m, 3 H) 7.32-7.44 (m, 1 H) 10.11-10.49 (m, 1 H). MS ESI/APCI Dual posi: 389[M + H]⁺, 411[M + Na]⁺. MS ESI/APCI Dual nega: 387[M − H]⁻. Example 1-69

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54- 2.70 (m, 2 H) 3.30-3.41 (m, 2 H) 4.15-4.23 (m, 2 H) 4.58-4.66 (m, 2 H) 7.15-7.24 (m, 2 H) 7.27-7.34 (m, 2 H) 10.06-10.50 (m, 1 H). MS ESI/APCI Dual posi: 389[M + H]⁺, 411[M + Na]⁺. MS ESI/APCI Dual nega: 387[M − H]⁻. Example 1-70

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3 H) 2.54-2.67 (m, 2 H) 3.32-3.38 (m, 2 H) 4.15-4.21 (m, 2 H) 4.52-4.58 (m, 2 H) 6.84-6.90 (m, 1 H) 6.99- 7.04 (m, 2 H)7.17-7.22 (m, 2 H) 7.62-7.67 (m, 1 H) 8.10 (d, J = 2.1 Hz, 1 H) 10.14-10.47 (m, 1 H). MS ESI/APCI Dual posi: 412[ M + H]⁺. MS ESI/APCI Dual nega: 410[M − H]⁻. Example 1-71

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.37- 1.45 (m, 3 H) 2.47-2.64 (m, 2 H) 3.26-3.38 (m, 2 H) 3.97-4.06 (m, 2 H) 4.15-4.23 (m, 2 H) 4.50-4.61 (m, 2 H) 6.83-6.89 (m, 2 H) 7.14-7.21 (m, 2 H) 10.24- 10.43 (m, 1 H). MS ESI/APCI Dual posi: 349[M + H]⁺, 371[M + Na]⁺. MS ESI/APCI Dual nega: 347[M − H]⁻. Example 1-72

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.48- 2.75 (m, 2 H) 3.25-3.48 (m, 2 H) 4.08-4.25 (m, 2 H) 4.45-4.65 (m, 2 H) 6.84-6.95 (m, 1 H) 7.10-7.16 (m, 2 H) 7.18-7.25 (m, 1 H) 7.36-7.45 (m, 2 H) 7.58-7.75 (m, 1 H) 8.03-8.22 (m, 1 H) 10.10-10.50 (m, 1 H). MS ESI/APCI Dual Posi: 398[M + H]⁺, 420[M + Na]⁺. MS ESI/APCI Dual nega: 396[M − H]⁻. Example 1-73

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.38-2.83 (m, 2 H) 3.50 (t, J = 7.1 Hz, 2 H) 4.03 (d, J = 5.1 Hz, 2 H) 4.60-4.76 (m, 2 H) 7.44-7.61 (m, 3 H) 7.94-8.15 (m, 4 H) 8.69 (s, 1 H) 9.87-10.08 (m, 1 H). MS ESI/APCI Dual posi: 382[M + H]⁺, 404[M + Na]⁺. MS ESI/APCI Dual nega: 380[M − H]⁻.

TABLE 21-11 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-74

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54- 2.72 (m, 2 H) 3.29-3.43 (m, 2 H) 4.13-4.24 (m, 2 H) 4.55-4.68 (m, 2 H) 7.37-7.45 (m, 1 H) 7.45-7.51 (m, 1 H) 7.56-7.61 (m, 1 H) 10.03-10.56 (m, 1 H). MS ESI/APCI Dual posi: 407[M + H]⁺, 429[M + Na]⁺. MS ESI/APCI Dual nega: 405[M − H]⁻. Example 1-75

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.03-2.29 (m, 1 H) 2.65-3.08 (m, 3 H) 3.67-3.88 (m, 1 H) 3.96-4.22 (m, 3 H) 4.96-5.16 (m, 1 H) 7.07-7.52 (m, 10 H) 7.58-7.70 (m, 4 H) 9.90-10.22 (m, 1 H) 12.76- 12.98 (m, 1 H). MS ESI/APCI Dual posi: 471[M + H]⁺, 493[M + Na]⁺. MS ESI/APCI Dual nega: 469[M − H]⁻. Example 1-76

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.77-1.95 (m, 2 H) 2.51-2.75 (m, 3 H) 3.07 (dd, J = 17.4, 7.0 Hz, 1 H) 3.50 (m, 1 H) 3.98-4.32 (m, 3 H) 4.98-5.12 (m, 1 H) 7.12-7.40 (m, 8 H) 7.42-7.51 (m, 2 H) 7.54-7.69 (m, 4 H) 9.90-10.20 (m, 1 H) 12.73-12.92 (m, 1 H). MS ESI/APCI Dual posi: 485[M + H]⁺, 507[M + Na]⁺. MS ESI/APCI Dual nega: 483[M − H]⁻. Example 1-77

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.17 (d, J = 6.2 Hz, 3 H) 2.37 (d, J = 17.3 Hz, 1 H) 3.04-3.19 (m, 1 H) 3.65-3.78 (m, 1 H) 3.95-4.09 (m, 2 H) 4.25 (d, J = 15.7 Hz, 1 H) 5.07 (d, J = 15.7 Hz, 1 H) 7.51 (d, J = 7.8 Hz, 2 H) 7.64 (br. s., 1 H) 7.89-8.36 (m, 4 H) 8.76 (d, J = 4.5 Hz, 1 H) 9.84-10.30 (m, 1 H). MS ESI/APCI Dual posi: 396[M + H]⁺. MS ESI/APCI Dual nega: 394[M − H]⁻. HCl Example 1-78

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15- 1.31 (m, 3 H) 2.26-2.41 (m, 1 H) 2.75-3.01 (m, 1 H) 3.49-3.63 (m, 1 H) 3.92-4.25 (m, 3 H) 5.17-5.40 (m, 1 H) 7.31-7.45 (m, 2 H) 7.54-7.67 (m, 2 H) 10.05- 10.41 (m, 1 H). MS ESI/APCI Dual posi: 387[M + H]⁺, 409[M + Na]⁺. MS ESI/APCI Dual nega: 385[M − H]⁻. Example 1-79

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16- 1.24 (m, 3 H) 2.20-2.38 (m, 4 H) 2.70-2.96 (m, 1 H) 3.49-3.64 (m, 1 H) 3.81-4.04 (m, 1 H) 4.15-4.23 (m, 2 H) 5.11-5.35 (m, 1 H) 7.09-7.20 (m, 4 H) 10.17- 10.39 (m, 1 H). MS ESI/APCI Dual Posi: 333[M + H]⁺, 355[M + Na]⁺. MS ESI/APCI Dual nega: 331[M − H]⁻. Example 1-80

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.03- 1.34 (m, 5 H) 1.36-2.01 (m, 7 H) 2.26-2.75 (m, 3 H) 2.87-3.11 (m, 1 H) 3.54-3.70 (m, 1 H) 3.84-4.02 (m, 1 H) 4.08-4.21 (m, 2 H) 7.13-7.35 (m, 5 H) 10.15- 10.35 (m, 1 H). MS ESI/APCI Dual posi: 401[M + H]⁺, 423[M + Na]⁺. MS ESI/APCI Dual nega: 399[M − H]⁻.

TABLE 21-12 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-81

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.62- 3.05 (m, 2 H) 3.58-4.36 (m, 4 H) 5.64-5.81 (m, 1 H) 7.27-7.49 (m, 5 H) 7.51-7.64 (m, 4 H) 9.88-10.45 (m,1 H). MS ESI/APCI Dual posi: 449[M + H]⁺, 471[M + Na]⁺. MS ESI/APCI Dual nega: 447[M − H]⁻. Example 1-82

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.90- 1.11 (m, 2 H) 1.16-1.26 (m, 1 H) 1.36-1.61 (m, 5 H) 1.67-1.86 (m, 2 H) 3.22 (s, 2 H) 4.13-4.23 (m, 2 H) 4.60-4.73 (m, 2 H) 7.37-7.47 (m, 2 H) 7.53-7.74 (m, 2 H) 9.99-10.52 (m, 1 H). MS ESI/APCI Dual posi: 441[M + H]⁺, 463[M + Na]⁺. MS ESI/APCI Dual nega: 4.39[M − H]⁻. Example 1-83

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.61- 1.78 (m, 2 H) 1.79-2.04 (m, 2 H) 2.38-2.57 (m, 2 H) 3.28-3.37 (m, 2 H) 4.13-4.22 (m, 2 H) 4.64-4.72 (m, 2 H) 7.36-7.44 (m, 2 H) 7.57-7.66 (m, 2 H) 10.19- 10.30 (m, 1 H). MS ESI/APCI Dual posi: 413[M + H]⁺, 435[M + Na]⁺. MS ESI/APCI Dual nega: 411[M − H]⁻. Example 1-84

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.03-1.81 (m, 10 H) 2.73-2.99 (m, 2 H) 3.19 (s, 3 H) 3.96-4.09 (m, 2 H) 4.76-4.95 (m, 2 H) 7.49-7.62 (m, 2 H) 7.79-7.92 (m, 2 H) 9.88-10.26 (m, 1H) 12.73-13.02 (m, 1 H). MS ESI/APCI Dual posi: 409[ M + Na]⁺. MS ESI/APCI Dual nega: 385[M − H]⁻. Example 1-85

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16-1.37 (m, 6 H) 2.49-2.70 (m, 2 H) 4.09-4.26 (m, 2 H) 4.62-4.79 (m, 2 H) 7.34-7.43 (m, 2 H) 7.49-7.66 (m, 2 H) 10.09- 10.47 (m, 1 H). MS ESI/APCI Dual posi: 401[M + H]⁺, 423[Na + H]⁺. MS ESI/APCI Dual nega: 399[M − H]⁻. Example 1-86

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.86- 1.08 (m, 2 H) 1.08-1.57 (m, 6 H) 1.61-1.82 (m, 2 H) 2.26-2.41 (m, 3 H) 3.09-3.25 (m, 2 H) 4.10-4.23 (m, 2 H) 4.49-4.66 (m, 2 H) 7.11-7.21 (m, 4 H) 10.31- 10.66 (m, 1 H). MS ESI/APCI Dual Posi: 387[M + H]⁺, 409[M + Na]⁺. MS ESI/APCI Dual nega: 385[M − H]⁻. Example 1-87

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.31 (s, 9 H)1.47- 1.60 (m, 2 H) 1.89-2.06 (m, 2 H) 2.88-3.13 (m, 2 H) 3.42- 3.57 (m, 2 H) 3.66-3.78 (m, 2 H) 3.97-4.11 (m, 2 H) 4.70- 4.88 (m, 2 H) 7.33-7.51 (m, 4 H) 7.52-7.65 (m, 4 H) 9.95- 10.27 (m, 1 H) 12.74-12.97 (m, 1 H). MS ESI/APCI Dual posi: 507[M + H]⁺, 529[M + Na]⁺. MS ESI/APCI Dual nega: 505[M − H]⁻.

TABLE 21-13 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-88

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.18-1.35 (m, 6 H) 2.23-2.37 (m, 3 H) 2.46-2.67 (m, 2 H) 4.10- 4.25 (m, 2 H) 4.57-4.71 (m, 2 H) 7.06-7.18 (m, 4 H) 10.21-10.46 (m, 1 H). MS ESI/APCI Dual posi: 347[M + H]⁺, 369[M + Na]⁺. MS ESI/APCI Dual nega: 345[M − H]⁻. Example 1-89

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.18- 1.37 (m, 2 H) 1.94-2.07 (m, 2 H) 2.30-2.38 (m, 3 H) 3.17-3.30 (m, 4 H) 3.64-3.76 (m, 2 H) 4.19 (d, J = 5.6 Hz, 2 H) 4.54-4.61 (m, 2 H) 7.12-7.19 (m, 4 H) 10.30-10.55 (m, 1 H). MS ESI/APCI Dual posi: 389[M + H]⁺, 411[M + Na]⁺. MS ESI/APCI Dual nega: 387[M − H]⁻. Example 1-90

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.49-1.68 (m, 2 H) 1.69-1.89 (m, 2 H) 2.16-2.31 (m, 5 H) 2.45-2.55 (m, 2 H) 3.44 (d, J = 4.0 Hz, 2 H) 4.48-4.57 (m, 2 H) 7.09-7.23 (m, 4 H). MS ESI/APCI Dual nega: 357[M − H]⁻. Na Example 1-91

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.05-1.73 (m, 10 H) 3.35-3.50 (m, 2 H) 3.94-4.11 (m, 2 H) 4.76- 4.94 (m, 2 H) 7.39-7.55 (m, 3 H) 7.81-8.02 (m, 3 H) 9.98-10.43 (m, 1 H). MS ESI/APCI Dual nega: 454[M − H]⁻. HCl Example 1-92

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.90-1.06 (m, 3 H) 2.28 (s, 3 H) 2.86-3.02 (m, 1 H) 3.21-3.58 (m, 4 H) 4.38-4.64 (m, 2 H) 7.07-7.22 (m, 4 H) 10.07- 10.30 (m, 1 H). MS ESI/APCI Dual posi: 355[M + Na]⁺. MS ESI/APCI Dual nega: 331[M − H]⁻. Na Example 1-93

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.95-1.17 (m, 3 H) 2.76-2.95 (m, 1 H) 3.08-3.23 (m, 1 H) 3.45-3.59 (m, 1 H) 3.96-4.11 (m, 2 H) 4.54-4.83 (m, 2 H) 7.43- 7.56 (m, 2 H) 7.62-7.74 (m, 1 H) 8.00-8.13 (m, 2 H) 8.14-8.33 (m, 2 H) 8.73-8.82 (m, 1 H) 9.99-10.39 (m, 1 H). MS ESI/APCI Dual posi: 396[M + H]⁺, 418[M + Na]⁺. MS ESI/APCI Dual nega: 394[M − H]⁻. HCl Example 1-94

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.16 (d, J = 6.4 Hz, 3 H) 2.26-2.45 (m, 1 H) 2.94-3.15 (m, 1 H) 3.75- 3.89 (m, 1 H) 3.99-4.09 (m, 2 H) 4.45-4.60 (m, 1 H) 4.98-5.12 (m, 1 H) 7.43-7.54 (m, 3 H) 7.85-7.98 (m, 3 H) 9.94 (br. s., 1 H). MS ESI/APCI Dual posi: 402[M + H]⁺. MS ESI/APCI Dual nega: 400[M − H]⁻. HCl

TABLE 21-14 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-95

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.71- 1.83 (m, 2 H) 1.87-2.04 (m, 2 H) 2.41-2.57 (m, 2 H) 3.42 (s, 2 H) 4.14-4.24 (m, 2 H) 4.75-4.86 (m, 2 H) 7.39-7.46 (m, 3 H) 7.78 (s, 1 H) 7.83-7.97 (m, 2 H) 10.10-10.27 (m, 1 H). MS ESI/APCI Dual posi: 428[M + H]⁺, 450[M + Na]⁺. MS ESI/APCI Dual nega: 426[M − H]⁻. Example 1-96

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28- 1.45 (m, 6 H) 2.47-2.63 (m, 2 H) 4.12-4.26 (m, 2 H) 4.71-4.90 (m, 2 H) 7.34-7.51 (m, 3 H) 7.74 (s, 1 H) 7.82-7.98 (m, 2 H) 10.11-10.51 (m, 1 H). MS ESI/APCI Dual posi: 416[M + H]⁺, 438[M + Na]⁺. MS ESI/APCI Dual nega: 414[M − H]⁻. Example 1-97

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23- 1.52 (m, 2 H) 1.90-2.15 (m, 2 H) 3.29-3.39 (m, 2 H) 3.44-3.58 (m, 2 H) 3.76-3.90 (m, 2 H) 4.15-4.25 (m, 2 H) 4.77-4.86 (m, 2 H) 7.40-7.47 (m, 3 H) 7.79 (s, 1 H) 7.84-7.95 (m, 2 H) 10.14-10.66 (m, 1 H). MS ESI/APCI Dual posi: 458[M + H]⁺, 480[M + Na]⁺. MS ESI/APCI Dual nega: 456[M − H]⁻. Example 1-98

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.48-1.67 (m, 2 H) 1.98-2.17 (m, 2 H) 2.81-3.09 (m, 2 H) 3.41-3.59 (m, 2 H) 3.68-3.81 (m, 2 H) 3.99-4.13 (m, 2 H) 4.85-5.03 (m, 2 H) 7.39-7.54 (m, 3 H) 7.81-7.99 (m, 3 H) 9.85-10.25 (m, 1H) 12.78-13.01 (m, 1 H). MS ESI/APCI Dual posi: 458[M + H]⁺. Example 1-99

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.99-1.49 (m, 4 H) 1.51-1.70 (m, 3 H) 1.72-2.09 (m, 6 H) 2.39-2.47 (m, 1 H) 2.78-3.05 (m, 2 H) 3.32-3.43 (m, 2 H) 3.44-3.61 (m, 2 H) 3.70-3.87 (m, 2 H) 3.92-4.10 (m, 2 H) 7.05-7.35 (m, 5 H) 10.03-10.21 (m, 1 H) 12.75-12.92 (m, 1 H). MS ESI/APCI Dual posi: 457[M + H]⁺. Example 1-100

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20- 1.32 (m, 3 H) 2.33 (dd, J = 17.2, 2.1 Hz, 1 H) 2.76- 3.04 (m, 1 H) 3.56-3.70 (m, 1 H) 3.92-4.15 (m, 1 H) 4.16-4.25 (m, 2 H) 5.21-5.42 (m, 1 H) 7.32-7.43 (m, 2 H) 7.52-7.62 (m, 2 H)7.63-7.74 (m, 4 H) 10.10- 10.41 (m, 1 H). MS ESI/APCI Dual Posi: 463[M + H]⁺, 485[M + Na]⁺. MS ESI/APCI Dual nega: 461[M − H]⁻. Example 1-101

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.02-1.77 (m, 10 H) 3.29-3.60 (m, 2 H) 3.98-4.11 (m, 2 H) 4.57- 4.80 (m, 2 H) 7.38-7.57 (m, 3 H) 7.96-8.15 (m, 4 H) 8.63-8.76 (m, 1 H) 10.08-10.42 (m, 1 H). MS ESI/APCI Dual posi: 472[M + Na]⁺. MS ESI/APCI Dual nega: 448[M − H]⁻. HCl

TABLE 21-15 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-102

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.66- 1.81 (m, 2 H)1.82-2.01 (m, 2 H) 2.42-2.55 (m, 2 H) 3.38 (s, 2 H) 4.14-4.20 (m, 2 H) 4.62-4.78 (m, 2 H) 7.39-7.54 (m, 2 H)7.60-7.74 (m, 1 H) 7.79-8.04 (m, 3 H) 8.14-8.30 (m, 1 H) 8.93-9.07 (m, 1 H) 10.13- 10.62 (m, 1 H). MS ESI/APCI Dual posi: 422[M + H]⁺, 444[M + Na]⁺. MS ESI/APCI Dual nega: 420[M − H]⁻. TFA Example 1-103

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.95-1.07 (m, 3 H) 2.48-2.78 (m, 1 H) 2.97-3.10 (m, 1 H) 3.36-3.45 (m, 1 H) 3.49-3.57 (m, 2 H) 4.56-4.75 (m, 2 H) 7.50 (d, J = 8.2 Hz, 2 H) 7.70 (d, J = 8.2 Hz, 2 H) 10.16 (br. s., 1 H). MS ESI posi: 387[M + H]⁺. Na Example 1-104

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.96-1.15 (m, 3 H) 2.63-2.95 (m, 1 H) 3.11-3.24 (m, 1 H) 3.47-3.62 (m, 1 H) 3.95-4.14 (m, 2 H) 4.65-4.97 (m, 2 H) 7.37- 7.56 (m, 3 H) 7.82-7.99 (m, 3 H) 9.90-10.39 (m, 1 H). MS ESI posi: 402[M + H]⁺. HCl Example 1-105

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.45-1.59 (m, 2 H) 1.88-2.05 (m, 2 H) 2.87-3.17 (m, 2 H) 3.42-3.58 (m, 2 H) 3.63-3.79 (m, 2 H) 3.95-4.11 (m, 2 H) 4.74- 4.97 (m, 2 H)7.45-7.57 (m, 2 H) 7.63-7.71 (m, 1 H) 7.97-8.08 (m, 2 H) 8.13-8.32 (m, 2 H) 8.72-8.81 (m, 1 H) 9.92-10.29 (m, 1 H). MS ESI/APCI Dual posi: 452[M + H]⁺. HCl Example 1-106

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.41-1.65 (m, 2 H) 1.82-2.04 (m, 2 H) 2.85-3.17 (m, 2 H) 3.41-3.59 (m, 2 H) 3.63-3.80 (m, 2 H) 3.94-4.13 (m, 2 H) 4.75- 4.97 (m, 2 H) 7.46-7.60 (m, 2 H) 7.61-7.76 (m, 2 H) 9.91-10.29 (m, 1 H) 12.63-13.13 (m, 1 H). MS ESI/APCI Dual posi: 443[M + H]⁺. MS ESI/APCI Dual mega: 441[M − H]⁻. Example 1-107

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.99- 2.12 (m, 12 H) 2.34-2.89 (m, 2 H) 3.02-3.57 (m, 4 H) 4.01-4.30 (m, 2 H) 6.94-7.48 (m, 5 H) 10.12-10.52 (m, 1 H). MS ESI/APCI Dual posi: 401[M + H]⁺, 423[M + Na]⁺. MS ESI/APCI Dual nega: 399[M − H]⁻. Example 1-108

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.03- 1.21 (m, 3 H)2.52-2.82 (m, 1 H) 3.07 (dd, J = 12.5, 8.0 Hz, 1 H) 3.40 (dd, J = 12.5, 5.8 Hz, 1 H) 4.15-4.24 (m, 2 H) 4.59-4.74 (m, 2 H) 7.32-7.43 (m, 2 H) 7.52-7.62 (m, 2 H) 7.60-7.75 (m, 4 H) 10.11-10.53 (m, 1 H). MS ESI/APCI Dual posi: 463[M + H]⁺, 485[M + Na]⁺. MS ESI/APCI Dual nega: 461[M − H]⁻ .

TABLE 21-16 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-109

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.25 (s, 6 H) 2.55- 2.80(m, 2H) 3.95-4.13 (m, 2 H) 4.64-4.84 (m, 2 H) 7.42- 7.63 (m, 3 H) 7.97-8.21 (m, 4 H) 8.70-8.77 (m, 1 H) 10.01-10.28 (m, 1 H). MS ESI/APCI Dual posi: 410[M + H]⁺, 432[M + Na]⁺. MS ESI/APCI Dual nega: 408[M − H]⁻. HCl Example 1-110

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17-1.41 (m, 2 H) 1.70-1.94 (m, 2 H) 3.35 (t, J = 11.0 Hz, 2 H) 3.45-3.54 (m, 2 H) 3.55-3.66 (m, 2 H) 3.97-4.12 (m, 2 H) 4.60-4.78 (m, 2 H) 7.44-7.66 (m, 3 H) 7.98-8.21 (m, 4 H) 8.74 (d, J = 4.8 Hz, 1 H) 10.08-10.37 (m, 1 H). MS ESI/APCI Dual posi: 452[M + H]⁺. MS ESI/APCI Dual nega: 450[M − H]⁻. HCl Example 1-111

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.06-1.80 (m, 10 H) 2.70-3.03 (m, 2 H) 3.93-4.14 (m, 2 H) 4.72-4.98 (m, 2 H) 7.43-7.59 (m, 2 H) 7.67-7.80 (m, 1 H) 7.96-8.13 (m, 2 H) 8.16-8.39 (m, 2 H) 8.73-8.84 (m, 1 H) 9.88-10.28 (m, 1 H) MS ESI/APCI Dual posi: 450[M + H]⁺. HCl Example 1-112

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.08-1.89 (m, 10 H) 2.83 (m, 2 H) 3.98-4.10 (m, 2 H) 4.75-5.02 (m, 2 H) 7.40- 7.53 (m, 3 H) 7.81-7.97 (m, 3 H) 9.85-10.13 (m, 1 H). MS ESI/APCI Dual posi: 456[M + H]⁺. HCl Example 1-113

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.52-2.79 (m, 2 H) 3.38 (t, J = 7.1 Hz, 2 H) 4.08-4.29 (m, 2 H) 4.65 (s, 2 H) 7.00-7.22 (m, 2 H) 7.47-7.67 (m, 1H) 9.87-10.41 (m, 1 H). MS ESI/APCI Dual posi: 391[M + H]⁺, 413[M + Na]⁺. MS ESI/APCI Dual nega: 389[M − H]⁻. Example 1-114

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.34 (m, 2 H) 1.33-1.58 (m, 2 H) 1.58-2.14 (m, 9 H) 2.39-2.65 (m, 3 H) 3.21-3.60 (m, 4 H) 4.08-4.25 (m, 2 H) 7.14-7.23 (m, 3 H) 7.23-7.33 (m, 2 H) 10.16-10.54 (m, 1 H). MS ESI/APCI Dual posi: 427[M + H]⁺, 449[M + Na]⁺. MS ESI/APCI Dual nega: 425[M − H]⁻. Example 1-115

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.08-1.53 (m, 10 H) 1.61-2.02 (m, 5 H) 2.41-2.61 (m, 3 H) 3.29 (dd, J = 17.2, 7.4 Hz, 2 H) 4.10-4.23 (m, 2 H) 7.13-7.22 (m, 3 H) 7.23-7.33 (m, 2 H) 10.18-10.46 (m, 1 H). MS ESI/APCI Dual posi: 415[M + H]⁺, 437[M + Na]⁺. MS ESI/APCI Dual nega: 413[M − H]⁻ .

TABLE 21-17 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-116

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.54-2.64 (m, 2 H) 3.36-3.54 (m, 4 H) 4.67 (s, 2 H) 7.45-7.61 (m, 2 H) 7.67 (d, J = 10.4 Hz, 1 H) 10.00 (br. s., 1 H). MS ESI/APCI Dual nega: 389[M − H]⁻. Na Example 1-117

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.02-1.23 (m, 2 H) 1.26-1.54 (m, 4 H) 1.62-1.99 (m, 8 H) 3.22-3.41 (m, 2 H) 3.51 (s, 2 H) 3.56-3.81 (m, 4 H) 3.96-4.05 (m, 2 H) 7.05-7.36 (m, 5 H) 10.19-10.31 (m, 1 H). MS ESI/APCI Dual posi: 479[M + Na]⁺. MS ESI/APCI Dual nega: 455[M − H]⁻. Example 1-118

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.25 (s, 6 H) 2.68-2.79 (m, 2 H) 3.95-4.08 (m, 2 H) 4.63-4.80 (m, 2 H) 7.39-7.48 (m, 2 H) 7.64-7.74 (m, 2 H) 7.76-7.84 (m, 2 H) 7.84-7.92 (m, 2 H) 9.98-10.29 (m, 1 H). MS ESI/APCI Dual posi: 497[M + Na]⁺. MS ESI/APCI Dual nega: 475[M − H]⁻. Example 1-119

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17-1.43 (m, 2 H) 1.65-1.94 (m, 2 H) 3.27-3.42 (m, 2 H) 3.44-3.54 (m, 2 H) 3.54-3.69 (m, 2 H) 3.98-4.08 (m, 2 H) 4.61- 4.75 (m, 2 H) 7.44-7.53 (m, 2 H) 7.70-7.78 (m, 2 H) 7.78-7.85 (m, 2 H) 7.85-7.93 (m, 2 H) 10.05-10.39 (m, 1 H). MS ESI/APCI Dual posi: 541[M + Na]⁺. MS ESI/APCI Dual nega: 517[M − H]⁻. Example 1-120

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.53- 2.80 (m, 2 H) 3.30-3.48 (m, 2 H) 4.09-4.30 (m, 2 H) 4.72 (s, 2 H) 7.60 (d, J = 7.9 Hz, 1 H) 7.74 (s, 1 H) 7.78-7.93 (m, 1 H) 9.75-10.65 (m, 1 H). MS ESI/APCI Dual posi: 463[M + Na]⁺. MS ESI/APCI Dual nega: 439[M − H]⁻. Example 1-121

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.57-1.90 (m, 4 H) 2.21-2.45 (m, 5 H) 2.74-3.01 (m, 2 H) 3.95-4.09 (m, 2 H) 4.73-4.88 (m, 2 H) 7.08-7.23 (m, 4 H) 9.92- 10.24 (m, 1 H) 12.78-12.97 (m, 1 H). MS ESI/APCI Dual posi: 359[M + H]⁺, 381[M + Na]⁺ ₋ Example 1-122

¹H NMR (300 MHz, DEUTERIUM OXIDE) δ ppm 1.60-2.09 (m, 4 H) 2.25-2.50 (m, 2 H) 2.82-3.02 (m, 2 H) 3.85-4.01 (m, 2 H) 4.81-5.04 (m, 2 H) 7.38- 7.58 (m, 2 H) 7.63-7.82 (m, 2 H). MS ESI/APCI Dual posi: 413[M + H]⁺. Na

TABLE 21-18 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-123

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.16-3.28 (m, 2 H) 3.95-4.12 (m, 2 H) 4.35-4.57 (m, 2 H) 4.78-4.93 (m, 2 H) 5.19 (s, 2 H) 7.38-7.56 (m, 3 H) 7.81-8.02 (m, 3 H) 9.68- 9.93 (m, 1 H). MS ESI/APCI Dual posi: 430[M + H]⁺, 452[M + Na]⁺. Example 1-124

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.01-3.32 (m, 2 H) 3.92-4.11 (m, 2 H) 4.36-4.52 (m, 2 H) 4.62-4.74 (m, 2 H) 5.06-5.21 (m, 2 H) 7.41-7.75 (m, 4 H) 9.72-10.36 (m, 1 H). MS ESI/APCI Dual posi: 415[M + H]⁺. MS ESI/APCI Dual nega: 413[M − H]⁻. Example 1-125

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.56-2.73 (m, 2 H) 3.34-3.46 (m, 2 H) 4.14-4.26 (m, 2 H) 4.59-4.69 (m, 2 H) 7.04-7.15 (m, 2 H) 7.33-7.48 (m, 4 H) 7.49-7.56 (m, 2 H) 10.11-10.50 (m, 1 H). MS ESI/APCI Dual posi: 421[M + Na]⁺. MS ESI/APCI Dual nega: 397[M − H]⁻. Example 1-126

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.53-2.75 (m, 2 H) 3.37-3.53 (m, 2 H) 4.09-4.23 (m, 2 H) 4.63-4.77 (m, 2 H) 7.08-7.17 (m, 2 H) 7.20-7.34 (m, 2 H) 7.37-7.44 (m, 1 H) 7.47-7.55 (m, 2 H) 10.10-10.47 (m, 1 H). MS ESI/APCI Dual posi: 417[M + H]⁺, 439[M + Na]⁺. MS ESI/APCI Dual nega: 415[M − H]⁻. Example 1-127

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.56-2.71 (m, 2 H) 3.41-3.52 (m, 2 H) 4.13-4.23 (m, 2 H) 4.66-4.74 (m, 2 H) 7.23-7.49 (m, 6 H) 7.51-7.58 (m, 2 H) 10.12- 10.45 (m, 1 H). MS ESI/APCI Dual posi: 399[M + H]⁺, 421[M + Na]⁺. MS ESI/APCI Dual nega: 397[M − H]⁻. Example 1-128

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.45-2.84 (m, 2H) 3.25-3.50 (m, 2 H) 4.10-4.28 (m, 2 H) 4.63 (s, 2 H) 7.10-7.35 (m, 1 H) 7.41 (s, 1 H) 7.57-7.81 (m, 1 H) 9.84- 10.63 (m, 1 H). MS ESI/APCI Dual posi: 407[M + H]⁺, 429[M + Na]⁺. MS ESI/APCI Dual nega: 405[M − H]⁻. Example 1-129

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.47 (s, 3 H) 2.53-2.73 (m, 2 H) 3.27-3.42 (m, 2 H) 4.09-4.26 (m, 2 H) 4.62 (s, 2 H) 7.18-7.39 (m, 2 H) 7.48 (s, 1 H) 9.95-10.56 (m, 1 H). MS ESI/APCI Dual posi: 387[M + H]⁺, 409[M + Na]⁺. MS ESI?APCI Dual nega: 385[M − H]⁻.

TABLE 21-19 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-130

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.58-1.94 (m, 4 H) 2.29-2.46 (m, 2 H) 2.79-3.06 (m, 2 H) 3.95-4.12 (m, 2 H) 4.85-5.01 (m, 2 H) 7.30-7.46 (m, 3 H) 7.82- 8.11 (m, 4 H) 8.62-8.70 (m, 1 H) 9.90-10.26 (m, 1 H). MS ESI/APCI Dual posi: 422[M + H]⁺, 444 [M + Na]⁺. MS ESI/APCI Dual nega: 420[M − H]⁻. Example 1-131

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.63-2.02 (m, 4 H) 2.21-2.50 (m, 2 H) 2.74-3.03 (m, 2 H) 3.93-4.11 (m, 2 H) 4.95-5.10 (m, 2 H) 7.42-7.53 (m, 3 H) 7.82- 7.99 (m, 3 H) 9.79-10.28 (m, 1 H). MS ESI/APCI Dual posi: 428[M + H]⁺, 450 [M + Na]⁺. Example 1-132

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00-1.68 (m, 5 H) 1.73-1.93 (m, 4 H) 2.38-2.49 (m, 1 H) 2.96-3.27 (m, 2 H) 3.52-3.74 (m, 2 H) 3.92-4.11 (m, 2 H) 4.33- 4.53 (m, 2 H)4.68-4.94 (m, 2 H) 7.06-7.33 (m, 5 H) 9.89-10.24 (m, 1 H) 12.67-13.09 (m, 1 H). MS ESI/APCI Dual posi: 429[M + H]⁺, 451 [M + Na]⁺. MS ESI/APCI Dual nega: 427[M − H]⁻. Example 1-133

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.06-3.42 (m, 2 H) 3.95-4.10 (m, 2H) 4.38-4.51 (m, 2 H) 4.68-4.81 (m, 2 H) 5.04-5.19 (m, 2 H) 7.39-7.49 (m, 2 H) 7.66- 7.76 (m, 2 H) 7.77-7.92 (m, 4 H) 9.79-10.33 (m, 1 H). MS ESI/APCI Dual posi: 491[M + H]⁺. Example 1-134

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.56- 2.74 (m, 2 H) 3.45 (t, J = 7.2 Hz, 2 H) 4.13-4.23 (m, 2 H) 4.65-4.78 (m, 2 H) 7.19-7.30 (m, 1 H) 7.31-7.40 (m, 1 H) 9.85-10.57 (m, 1 H). MS ESI/APCI Dual posi: 431[M + Na]⁺. MS ESI/APCI Dual nega: 407[M − H]⁻. Example 1-135

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.53- 2.68 (m, 2 H) 3.46 (t, J = 7.0 Hz, 2 H) 4.11-4.19 (m, 2 H) 4.68-4.76 (m, 2 H) 7.16-7.23 (m, 2 H) 9.90- 10.52 (m, 1 H). MS ESI/APCI Dual posi: 431[M + Na]⁺. MS ESI/APCI Dual nega: 407[M − H]⁻. Example 1-136

¹H NMR (600 MHz, METHANOL-d₄) δ ppm 2.56- 2.63 (m, 2 H) 3.37 (t, J = 7.2 Hz, 2 H) 3.89 (s, 2 H) 4.64 (s, 2 H) 6.14-6.42 (m, 1 H) 7.15-7.25 (m, 2 H) 7.33-7.42 (m, 2 H). MS ESI/APCI Dual posi: 443[M + Na]⁺. MS ESI/APCI Dual nega: 419[M − H]⁻. Na

TABLE 21-20 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-137

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.01-1.62 (m, 5 H) 1.64-2.02 (m, 8 H) 2.28-2.48 (m, 3 H) 2.66-2.98 (m, 2 H) 3.35-3.54 (m, 2 H) 3.91-4.08 (m, 2 H) 7.06- 7.34 (m, 5 H) 9.99-10.18 (m, 1 H) 12.66-13.03 (m, 1 H). MS ESI/APCI Dual posi: 427[M + H]⁺, 449[M + Na]⁺. Example 1-138

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.31 (s, 9 H) 3.29-3.34 (m, 2 H) 3.95-4.11 (m, 2 H) 4.36-4.49 (m, 2 H) 4.69-4.81 (m, 2 H) 5.00-5.15 (m, 2 H) 7.30- 7.42 (m, 2 H) 7.43-7.50 (m, 2 H) 7.51-7.66 (m, 4 H) 9.84-10.33 (m, 1 H). MS ESI/APCI Dual posi: 479[M + H]⁺, 501[M + Na]⁺. Example 1-139

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.51- 2.68 (m, 2 H) 3.27-3.38 (m, 2 H) 4.14-4.22 (m, 2 H) 4.53-4.65 (m, 2 H) 6.98-7.08 (m, 2 H) 7.18-7.31 (m, 2 H) 10.08-10.53 (m, 1 H). MS ESI/APCI Dual posi: 345[M + Na]⁺. MS ESI/APCI Dual nega: 321[M − H]⁻. Example 1-140

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.46-2.63 (m, 2 H) 3.31-3.40 (m, 2H) 3.43-3.54 (m, 2 H) 4.66 (s, 2 H) 7.52 (d, J = 8.3 Hz, 2 H) 7.66 (d, J = 8.3 Hz, 2 H). MS ESI/APCI Dual nega: 421[M − H]⁻. Na Example 1-141

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.07-1.21 (m, 1 H) 1.29-1.43 (m, 2 H) 1.48-1.61 (m, 5 H) 1.61-1.71 (m, 2 H) 2.79 (br. s., 2 H) 3.42-3.53 (m, 2 H) 4.84 (br. s., 2 H) 7.82 (d, J = 7.8 Hz, 1 H) 7.95 (d, J = 7.8 Hz, 1 H) 8.71 (s, 1 H). MS ESI/APCI Dual nega: 440[M − H]⁻. Na Example 1-142

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.08-1.21 (m, 1 H) 1.31-1.45 (m, 2 H) 1.48-1.63 (m, 5 H) 1.64-1.75 (m, 2 H) 2.66-3.09 (m, 2 H) 3.95-4.08 (m, 2 H) 4.84- 4.96 (m, 2 H) 7.39-7.73 (m, 1 H) 7.98-8.22 (m, 1 H) 8.89 (s, 1 H) 9.79-10.27 (m, 1 H). MS ESI/APCI Dual nega: 440[M − H]⁻. Example 1-143

cis-trans mixture ¹H NMR (600 MHz, METHANOL-d₄) δ ppm 1.05- 1.86 (m, 7 H) 2.03-2.46 (m, 2 H) 3.36-3.44 (m, 1 H) 3.78-3.84 (m, 2 H) 4.15-4.30 (m, 1 H) 5.14-5.26 (m, 1 H) 7.32-7.73 (m, 4 H). MS ESI/APCI Dual posi: 449[M + Na]⁺. MS ESI/APCI Dual nega: 425[M − H]⁻. Na

TABLE 21-21 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-144

¹H NMR (600 MHz, METHANOL-d₄) δ ppm 1.09 (d, J = 7.0 Hz, 3 H) 2.55-2.69 (m, 1 H) 3.04 (dd, J = 12.6, 8.1 Hz, 1 H) 3.41 (dd, J = 12.6, 5.6 Hz, 1 H) 3.89 (s, 2 H) 4.52 (d, J = 15.1 Hz, 1 H) 4.64 (d, J = 15.1 Hz, 1 H) 7.24 (d, J = 8.5 Hz, 2 H) 7.48 (d, J = 8.5 Hz, 2 H). MS ESI/APCI Dual posi: 419[M + H]⁺. MS ESI/APCI Dual nega: 395[M − H]⁻. Na Example 1-145

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.49-2.64 (m, 2 H) 3.30-3.41 (m, 2 H) 3.49 (d, J = 4.5 Hz, 2 H) 4.55 (s, 2 H) 7.28 (t, J = 8.1 Hz, 1 H) 7.39 (dd, J = 8.1, 1.7 Hz, 1 H) 7.54 (dd, J = 9.5, 1.7 Hz, 1 H). MS ESI/APCI Dual nega: 399[M − H]⁻. Na Example 1-146

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.52-1.64 (m, 3 H) 2.43-2.58 (m, 2 H) 2.91-3.01 (m, 1 H) 3.23-3.35 (m, 1 H) 4.15-4.25 (m, 2 H) 5.83-6.09 (m, 1 H) 7.38-7.51 (m, 2 H) 7.56-7.67 (m, 2 H) 10.08-10.52 (m, 1 H). MS ESI/APCI Dual posi: 409[M + Na]⁺. MS ESI/APCI Dual nega: 385[M − H]⁻. Example 1-147

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.62-0.96 (m, 2 H) 1.03-1.31 (m, 2H) 3.32-3.40 (m, 2 H) 3.98-4.08 (m, 2 H) 4.62-4.76 (m, 2 H) 7.45-7.56 (m, 2 H) 7.68-7.80 (m, 2 H) 10.01-10.42 (m, 1 H). MS ESI/APCI Dual posi: 399[M + H]⁺, 421 [M + Na]⁺. MS ESI/APCI Dual nega: 397[M − H]⁻. Example 1-148

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.03-1.16 (m, 3 H) 2.13-2.28 (m, 1 H) 2.77-2.97 (m, 1 H) 3.45-3.64 (m, 3 H) 4.03-4.18 (m, 1 H) 4.88-5.01 (m, 1 H) 7.22-7.31 (m, 2 H) 7.45-7.57 (m, 2 H) 9.90-10.19 (m, 1 H). MS ESI/APCI Dual posi: 397[M + H]⁺, 419[M + Na]⁺. Na Example 1-149

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.07-1.16 (m, 3 H) 2.15-2.30 (m, 1 H) 2.84-3.04 (m, 1 H) 3.52-3.68 (m, 3 H) 4.17 (d, J = 15.5 Hz, 1 H) 5.00 (d, J = 15.5 Hz, 1 H) 7.26- 7.37 (m, 2 H) 7.38-7.48 (m, 2 H) 9.96-10.15 (m, 1 H). MS ESI/APCI Dual posi: 403[M + H]⁺. Na Example 1-150

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.21 (s, 6 H) 2.52-2.77 (m, 2 H) 3.94-4.11 (m, 2 H) 4.54-4.71 (m, 2 H) 7.20- 7.33 (m, 2 H) 7.42-7.58 (m, 2 H) 9.96-10.27 (m, 1 H). MS ESI/APCI Dual posi: 411[M + H]⁺.

TABLE 21-22 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-151

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.22 (s, 6 H) 2.54- 2.78 (m, 2 H) 3.92-4.09 (m, 2 H) 4.59-4.77 (m, 2 H) 7.23- 7.36 (m, 2 H) 7.36-7.48 (m, 2 H) 9.95-10.27 (m, 1 H). MS ESI/APCI Dual posi: 417[M + H]⁺. Example 1-152

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.49-2.60 (m, 2 H) 3.27-3.33 (m, 2 H) 3.50 (d, J = 4.5 Hz, 2 H) 4.56 (s, 2 H) 7.05-7.22 (m, 1 H) 7.26-7.46 (m, 2 H) 9.91-10.24 (m, 1 H). MS ESI/APCI Dual posi: 385[M + H]⁺. MS ESI/APCI Dual nega: 383[M − H]⁻. Na Example 1-153

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.91 (t, J = 7.2 Hz, 3 H) 1.82-2.16 (m, 2 H) 2.22-2.47 (m, 1 H) 2.79-2.95 (m, 1 H) 3.14-3.35 (m, 2 H) 3.49 (d, J = 4.5 Hz, 2 H) 5.67 (dd, J = 10.1, 5.9 Hz, 1 H) 7.55 (d, J = 8.2 Hz, 2 H) 7.70 (d, J = 8.2 Hz, 2 H) 10.10 (br. s., 1 H). MS ESI/APCI Dual nega: 399[M − H]⁻. Na Example 1-154

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.63-1.87 (m, 2 H) 1.88-2.07 (m, 2 H) 2.24-2.46 (m, 2 H) 2.76-2.98 (m, 2 H) 4.10-4.26 (m, 2 H) 4.78-4.91 (m, 2 H) 7.13-7.22 (m, 2 H) 7.23-7.32 (m, 2 H) 10.02-10.44 (m, 1 H). MS ESI/APCI Dual posi: 451[M + Na]⁺. MS ESI/APCI Dual nega: 427[M − H]⁻. Example 1-155

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.61-1.82 (m, 2 H) 1.87-2.02 (m, 2 H) 2.24-2.44 (m, 2 H) 2.77-2.91 (m, 2 H) 4.14-4.21 (m, 2 H) 4.74-4.86 (m, 2 H) 7.04-7.20 (m, 2 H) 7.38-7.50 (m, 2 H) 10.04-10.42 (m, 1 H). MS ESI/APCI Dual posi: 445[M + Na]⁺. MS ESI/APCI Dual nega: 421[M − H]⁻. Example 1-156

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.53-1.93 (m, 8 H) 2.59-2.75 (m, 2 H) 4.08-4.27 (m, 2 H) 4.58-4.75 (m, 2 H) 7.31-7.40 (m, 2 H) 7.54-7.63 (m, 2 H) 9.98-10.49 (m, 1 H). MS ESI/APCI Dual posi: 449[M + Na]⁺. MS ESI/APCI Dual nega: 425[M − H]⁻. Example 1-157

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.21 (s, 6 H) 2.52- 2.76 (m, 2 H) 3.95-4.10 (m, 2 H) 4.56-4.74 (m, 2 H) 7.25- 7.43 (m, 4 H) 9.98-10.27 (m, 1 H) 12.86 (br. s., 1 H). MS ESI/APCI Dual posi: 367[M + H]⁺. MS ESI/APCI Dual nega: 365[M − H]⁻.

TABLE 21-23 Com- Salt pound infor- No. Structure Analytical Data mation Example 1-158

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.18 (s, 6 H) 2.50- 2.68 (m, 2 H) 3.48-3.58 (m, 2 H) 4.61 (s, 2 H) 7.24-7.33 (m, 1 H) 7.49-7.60 (m, 2 H) 9.92-10.24 (m, 1 H). MS ESI/APCI Dual posi: 401[M + H]⁺. MS ESI/APCI Dual nega: 399[M − H]⁻. Na Example 1-159

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.57-2.7 (m, 2 H) 3.34-3.41 (m, 2 H) 4.15-4.23 (m, 2 H) 4.57-4.63 (m, 2 H) 7.18-7.24 (m, 1 H) 7.27-7.33 (m, 1 H) 7.37-7.41 (m, 1 H) 10.01-10.58 (m, 1 H). MS ESI/APCI Dual posi: 445[M + Na]⁺. MS ESI/APCI Dual nega: 421[M − H]⁻. Example 1-160

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.55- 2.69 (m, 2 H) 3.32-3.40 (m, 2 H) 4.15-4.22 (m, 2 H) 4.57-4.63 (m, 2 H) 7.15-7.21 (m, 1 H) 7.21-7.28 (m, 1 H) 7.40-7.50 (m, 1 H) 9.92-10.55 (m, 1 H). MS ESI/APCI Dual posi: 455[M + Na]⁺. MS ESI/APCI Dual nega: 421[M − H]⁻. Example 1-161

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.17 (s, 6 H) 3.29-3.36 (m, 2 H) 3.46 (d, J = 4.1 Hz, 2 H) 4.60 (br. s., 2 H) 7.00-7.40 (m, 5 H). MS ESI/APCI Dual posi: 421[M + Na]⁺. MS ESI/APCI Dual nega: 397[M − H]⁻. Na Example 1-162

¹H NMR (600 MHz, METHANOL-d₄) δ ppm 1.03-1.18 (m, 3 H) 2.58-2.69 (m, 1 H) 3.00-3.07 (m, 1 H)3.38- 3.44 (m, 1 H) 3.88 (s, 2 H) 4.53 (d, J = 15.1Hz, 1 H) 4.66 (d, J = 15.1 Hz, 1 H) 7.25-7.38 (m, 4 H). MS ESI/APCI Dual posi: 375[M + Na]⁺. MS ESI/APCI Dual nega: 351[M − H]⁻. Na Example 1-163

¹H NMR (600 MHz, METHANOL-d₄) δ ppm 1.05-1.18 (m, 3 H) 2.60-2.68 (m, 1 H) 3.06 (dd, J = 12.6, 7.6 Hz, 1 H) 3.44 (dd, J = 12.6, 5.4 Hz, 1 H) 3.89 (s, 2 H) 4.50- 4.58 (m, 1 H) 4.61-4.68 (m, 1 H) 7.26 (dd, J = 8.3, 2.1 Hz, 1 H) 7.44-7.52 (m, 2 H). MS ESI/APCI Dual posi: 409[M + Na]⁺. MS ESI/APCI Dual nega: 385[M − H]⁻. Na Example 1-164

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.18 (s, 6 H) 2.53- 2.61 (m, 2 H) 3.47-3.55 (m, 2 H) 4.63 (s, 2 H) 7.38 (dd, J = 8.5, 2.0 Hz, 1 H) 7.46-7.52 (m, 1 H) 7.56 (d, J = 2.0 Hz, 1 H) 9.99-10.19 (m, 1 H). MS ESI/APCI Dual posi: 451[M + H]⁺. MS ESI/APCI Dual nega: 449[M − H]⁻. Na

TABLE 21-24 Compound Salt No. Structure Analytical Data information Example 1-165

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17 (s, 6 H) 2.50-2.59 (m, 2 H) 3.46-3.56 (m, 2 H) 4.66 (s, 2 H) 7.37 (dd, J = 8.4, 1.9 Hz, 1 H) 7.43-7.50 (m, 1 H) 7.61 (d, J = 8.4 Hz, 1 H) 10.07 (br. s., 1 H). MS ESI/APCI Dual posi: 451 [M + H]⁺. MS ESI/APCI Dual nega: 449 [M − H]⁻. Na Example 1-166

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 1.59-1.77 (m, 2 H) 1.78-1.94 (m, 2 H) 2.22-2.39 (m, 2 H) 2.56-2.76 (m, 2 H) 3.87 (s, 2 H) 4.85 (s, 2 H) 7.28 (s, 4 H). MS ESI/APCI Dual posi: 401 [M + Na]⁺. MS ESI/APCI Dual nega: 377 [M − H]⁻. Na Example 1-167

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 1.66-1.83 (m, 2 H) 1.83-1.99 (m, 2 H) 2.29-2.46 (m, 2 H) 2.86 (s, 2 H) 3.88 (s, 2 H) 4.86 (s, 2 H) 7.23 (dd, J = 8.2, 2.2 Hz, 1 H) 7.40- 7.49 (m, 2H). MS ESI/APCI Dual posi: 435 [M + Na]⁺. MS ESI/APCI Dual nega: 411 [M − H]⁻. Na Example 1-168

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.22-1.32 (m, 6 H) 1.84-1.96 (m, 3 H) 2.51-2.66 (m, 2 H) 4.14-4.22 (m, 2 H) 4.64-4.77 (m, 2 H) 7.27-7.36 (m, 2 H) 7.41-7.50 (m, 2 H) 10.12-10.50 (m, 1 H). MS ESI/APCI Dual posi: 397 [M + H]⁺, 419 [M + Na]⁺. MS ESI/APCI Dual nega: 395 [M − H]⁻. Example 1-169

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.20-1.31 (m, 6 H) 2.48-2.64 (m, 2 H) 3.82-3.89 (m, 3 H) 4.14-4.23 (m, 2 H) 4.55-4.68 (m, 2 H) 6.90-6.98 (m, 1 H) 7.11-7.22 (m, 2 H) 10.12-10.50 (m, 1 H). MS ESI/APCI Dual posi: 447 [M + H]⁺, 469 [M + Na]⁺. MS ESI/APCI Dual nega: 445 [M − H]⁻. Example 1-170

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.19-1.37 (m, 6 H) 2.17-2.35 (m, 6 H) 2.48-2.69 (m, 2 H) 4.07-4.25 (m, 2 H) 4.48-4.67 (m, 2 H) 6.09-6.48 (m, 1 H) 6.84-7.00 (m, 2 H) 10.11-10.48 (m, 1 H). MS ESI/APCI Dual posi: 427 [M + H]⁺, 449 [M + Na]⁺. MS ESI/APCI Dual nega: 425 [M − H]⁻. Example 1-171

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.06-1.14 (m, 3 H) 2.13- 2.25 (m, 1 H) 2.80-2.98 (m, 1 H) 3.47-3.63 (m, 3 H) 4.05- 4.21 (m, 1 H) 4.92-5.01 (m, 1 H) 7.27-7.43 (m, 4 H) 10.05 (br. s., 1 H). MS ESI/APCI Dual posi: 353 [M + H]⁺. Na

TABLE 21-25 Compound Salt No. Structure Analytical Data information Example 1-172

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15-1.30 (m, 3 H) 2.09-2.44 (m, 1 H) 2.76-3.01 (m, 1 H) 3.46-3.66 (m, 1 H) 3.82-4.05 (m, 1 H) 4.07-4.25 (m, 2 H) 5.04-5.26 (m, 1 H) 7.04-7.20 (m, 1 H) 7.31-7.49 (m, 2 H) 9.97-10.33 (m, 1 H). MS ESI/APCI Dual posi: 387 [M + H]⁺. MS ESI/APCI Dual nega: 385 [M − H]⁻. Example 1-173

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.29-2.50 (m, 2 H) 2.90 (t, J = 6.8 Hz, 2 H) 3.29-3.35 (m, 2 H) 3.45 (d, J = 4.5 Hz, 2 H) 3.57 (br. s., 2 H) 7.46-7.70 (m, 4 H). MS ESI/APCI Dual posi: 387 [M + H]⁺, 409 [M + Na]⁺. MS ESI/APCI Dual nega: 385 [M − H]⁻. Na Example 1-174

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.99-1.22 (m, 6 H) 2.98-3.12 (m, 2 H) 4.13-4.25 (m, 2 H) 4.60-4.73 (m, 2 H) 7.33-7.50 (m, 2 H) 7.54-7.68 (m, 2 H) 10.19-10.65 (m, 1 H). MS ESI/APCI Dual posi: 401 [M + H]⁺, 423 [M + Na]⁺. MS ESI/APCI Dual nega: 399 [M − H]⁻. Example 1-175

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 1.02-1.27 (m, 12 H) 3.82-3.93 (m, 2 H) 4.80-4.87 (m, 2 H) 7.43-7.67 (m, 4 H). MS ESI/APCI Dual posi: 429 [M + H]⁺, 451 [M + Na]⁺. MS ESI/APCI Dual nega: 427 [M − H]⁻. Na Example 1-176

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.41-2.53 (m, 2 H) 2.84-2.97 (m, 2 H) 3.29-3.36 (m, 2 H) 3.44 (d, J = 4.1 Hz, 2 H) 3.57 (br. s., 2 H) 7.50 (d, J = 8.0 Hz, 2 H) 7.66 (d, J = 8.0 Hz, 2 H). MS ESI/APCI Dual nega: 385 [M − H]⁻. Na Example 1-177

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.13 (d, J = 6.6 Hz, 3 H) 2.10-2.34 (m, 1 H) 2.76-3.03 (m, 1 H) 3.51 (d, J = 4.5 Hz, 2 H) 3.62 (d, J = 5.0 Hz, 1 H) 4.00-4.28 (m, 1 H) 5.05 (d, J = 15.3 Hz, 1 H) 7.24-7.32 (m, 2 H) 7.39 (d, J = 7.8 Hz, 2 H) 7.61 (d, J = 8.3 Hz, 2 H) 7.66-7.73 (m, 2 H). MS ESI/APCI Dual posi: 413 [M + H]⁺. MS ESI/APCI Dual nega: 411 [M − H]⁻. Na Example 1-178

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.70-1.82 (m, 2 H) 1.93-2.01 (m, 2 H) 2.36-2.46 (m, 2 H), 2.82-2.94 (m, 2 H) 4.14-4.22 (m, 2 H) 4,81-4.97 (m, 2 H) 7.08-7.15 (m, 2 H) 7.27-7.34 (m, 2 H) 7.46-7.55 (m, 4 H) 10.03- 10.46 (m, 1 H). MS ESI/APCI Dual posi: 439 [M + H]⁺, 461 [M + Na]⁺. MS ESI/APCI Dual nega: 437 [M − H]⁻.

TABLE 21-26 Compound Salt No. Structure Analytical Data information Example 1-179

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17- 1.39 (m, 6 H) 2.12-2.33 (m, 3 H) 2.48-2.68 (m, 2 H) 4.10-4.25 (m, 2 H) 4.50-4.67 (m, 2 H) 6.88-7.12 (m, 3 H) 10.17-10.44 (m, 1 H). MS ESI/APCI Dual posi: 365 [M + H]⁺, 387 [M + Na]⁺. MS ESI/APCI Dual nega: 363 [M − H]⁻. Example 1-180

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.18 (s, 6 H) 2.31 (s, 3 H) 2.39-2.62 (m, 2 H) 3.47 (d, J = 4.4 Hz, 2 H) 4.58 (br. s., 2 H) 7.13 (d, J = 8.2 Hz, 1 H) 7.25 (s, 1 H) 7.32 (d, J = 8.2 Hz, 1 H) 10.02 (br. s., 1 H). MS ESI/APCI Dual posi: 403 [M + Na]⁺. MS ESI/APCI Dual nega: 379 [M − H]⁻. Na Example 1-181

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.33-2.48 (m, 1 H) 2.60-2.87 (m, 2 H) 2.91-3.04 (m, 1 H) 3.46-3.61 (m, 1 H) 3.62-3.77 (m, 1 H) 4.18-4.26 (m, 2 H) 5.16-5.45 (m, 1 H) 7.02-7.16 (m, 2 H) 7.27-7.40 (m, 5 H) 7.55-7.64 (m, 2 H) 9.98-10.47 (m, 1 H). MS ESI/APCI Dual posi: 463 [M + H]⁺, 485 [M + Na]⁺. MS ESI/APCI Dual nega: 461 [M − H]⁻. Example 1-182

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.92 (t, J = 7.5 Hz, 3 H) 1.62-1.75 (m, 2 H) 2.42-2.54 (m, 1 H) 2.74- 2.94 (m, 1 H) 3.22-3.33 (m, 1 H) 3.90-4.10 (m, 1 H) 4.14- 4.25 (m, 2 H) 5.28-5.47 (m, 1 H) 7.35-7.43 (m, 2 H) 7.56- 7.65 (m, 2 H) 10.01-10.38 (m, 1 H). MS ESI/APCI Dual posi: 401 [M + H]⁺, 423 [M + Na]⁺. MS ESI/APCI Dual nega: 399 [M − H]⁻. Example 1-183

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.74-0.94 (m, 6 H) 1.57-1.81 (m, 4 H) 2.56-2.72 (m, 2 H) 4.10-4.24 (m, 2 H) 4.64-4.79 (m, 2 H) 7.30-7.44 (m, 2 H) 7.49-7.67 (m, 2 H) 10.09-10.34 (m, 1 H). MS ESI/APCI Dual posi: 429 [M + H]⁺, 451 [M + Na]⁺. MS ESI/APCI Dual nega: 427 [M − H]⁻. Example 1-184

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17 (s, 6 H) 2.16- 2.22 (m, 3 H) 2.49-2.59 (m, 2 H) 3.43-3.53 (m, 2 H) 4.59 (s, 2 H) 6.98-7.07 (m, 2 H) 7.15-7.25 (m, 1 H) 9.97-10.24 (m, 1 H). MS ESI/APCI Dual posi: 365 [M + H]⁺. MS ESI/APCI Dual nega: 363 [M − H]⁻. Na Example 1-185

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.79-2.13 (m, 2 H) 2.39-2.56 (m, 2 H) 2.68-2.92 (m, 2 H), 3.21-3.35 (m, 1 H) 3.71-3.93 (m, 1 H) 4.15-4.25 (m, 2 H) 5.17-5.37 (m, 1 H) 7.06-7.35 (m, 7 H) 7.48-7.57 (m, 2 H) 10.05-10.13 (m, 1 H). MS ESI/APCI Dual posi: 477 [M + H]⁺, 499 [M + Na]⁺. MS ESI/APCI Dual nega: 475 [M − H]⁻.

TABLE 21-27 Compound Salt No. Structure Analytical Data information Example 1-186

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22-1.30 (m, 6 H) 1.95-2.11 (m, 2 H) 2.20-2.42 (m, 2 H) 2.45-2.63 (m, 2 H) 3.90-4.08 (m, 2 H) 4.12-4.26 (m, 2 H) 4.55-4.71 (m, 2 H) 6.78-6.88 (m, 2 H) 7.15-7.24 (m, 2 H) 10.21-10.47 (m, 1 H). MS ESI/APCI Dual posi: 481 [M + Na]⁺. MS ESI/APCI Dual nega: 457 [M − H]⁻. Example 1-187

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21-1.35 (m, 6 H) 1.97-2.13 (m, 2 H) 2.17-2.24 (m, 3 H) 2.23-2.44 (m, 2 H) 2.49-2.64 (m, 2 H) 3.92-4.07 (m, 2 H) 4.14-4.24 (m, 2 H) 4.53-4.65 (m, 2 H) 6.65-6.77 (m, 1 H) 6.96-7.10 (m, 2 H) 10.25-10.42 (m, 1 H). MS ESI/APCI Dual posi: 495 [M + Na]⁺. MS ESI/APCI Dual nega: 471 [M − H]⁻. Example 1-188

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26-1.30 (m, 6 H) 2.52-2.68 (m, 2 H) 4.15-4.24 (m, 2 H) 4.51-4.68 (m, 5 H) 4.75-4.80 (m, 2 H) 7.00-7.07 (m, 1 H) 7.09-7.17 (m, 1 H) 7.27-7.33 (m, 1 H) 10.10-10.36 (m, 1 H). MS ESI/APCI Dual posi: 483 [M + Na]⁺. MS ESI/APCI Dual nega: 459 [M − H]⁻. Example 1-189

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.07 (s, 6 H) 2.10- 2.21 (m, 5 H) 3.43 (d, J = 4.4 Hz, 2 H) 4.40-4.87 (m, 7 H) 6.86-6.99 (m, 1 H) 6.99-7.11 (m, 2 H) 10.07-10.20 (m, 1 H). MS ESI/APCI Dual posi: 463 [M + Na]⁺. MS ESI/APCI Dual nega: 439 [M − H]⁻. Na Example 1-190

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.68-0.81 (m, 2 H) 0.98-1.09 (m, 2 H) 2.15-2.25 (m, 1 H) 2.54-2.68 (m, 2 H) 3.26-3.38 (m, 2 H) 4.15-4.25 (m, 2 H) 4.55 -4.65 (m, 2 H) 6.92 (s, 1 H) 7.09-7.17 (m, 1 H) 7.45-7.74 (m, 1 H) 9.98-10.64 (m, 1 H). MS ESI/APCI Dual posi: 413 [M + H]⁺. MS ESI/APCI Dual nega: 411 [M − H]⁻. Example 1-191

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.21-1.34 (m, 6 H) 2.54-2.67 (m, 2 H) 3.83-3.92 (m, 3 H) 4.08-4.23 (m, 2 H) 4.61-4.76 (m, 2 H) 3.83-3.92 (m, 3 H) 4.08-4.23 (m, 2 H) 4.61-4.76 (m, 2 H) 6.84-6.95 (m, 2 H) 7.45-7.54 (m, 1 H) 9.99-10.45 (m, 1 H). MS ESI/APCI Dual posi: 431 [M + H]⁺, 453 [M + Na]⁺. MS ESI/APCI Dual nega: 429 [M − H]⁻. Example 1-192

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.24-1.34 (m, 6 H) 2.55-2.69 (m, 2 H) 4.15-4.23 (m, 2 H) 4.62-4.77 (m, 2 H) 6.36-6.69 (m, 1 H) 7.16-7.29 (m, 2 H) 7.58-7.67 (m, 1 H) 9.91-10.55 (m, 1 H). MS ESI/APCI Dual posi: 467 [M + H]⁺, 489 [M + Na]⁺. MS ESI/APCI Dual nega: 465 [M − H]⁻.

TABLE 21-28 Compound Salt No. Structure Analytical Data information Example 1-193

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23-1.30 (m, 6 H) 2.47-2.65 (m, 2 H) 3.71-3.83 (m, 3 H) 4.09-4.25 (m, 2 H) 4.59-4.72 (m, 2 H) 6.54-6.71 (m, 2 H) 7.18-7.24 (m, 1 H) 10.17-10.43 (m, 1 H). MS ESI/APCI Dual posi: 403 [M + Na]⁺. MS ESI/APCI Dual nega: 379 [M − H]⁻. Example 1-194

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.19-1.33 (m, 6 H) 2.49-2.64 (m, 2 H) 3.82-3.91 (m, 3 H) 4.12-4.25 (m, 2 H) 4.52-4.65 (m, 2 H) 6.82-7.12 (m, 3 H) 10.17- 10.44 (m, 1 H). MS ESI/APCI Dual posi: 403 [M + Na]⁺. MS ESI/APCI Dual nega: 379 [M − H]⁻. Example 1-195

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17-1.36 (m, 6 H) 2.48-2.64 (m, 2 H) 3.82-3.93 (m, 3 H) 4.14-4.26 (m, 2 H) 4.52-4.64 (m, 2 H) 6.84-6.92 (m, 1 H) 7.10-7.19 (m, 1 H) 7.25-7.32 (m, 1 H) 10.18-10.45 (m, 1 H). MS ESI/APCI Dual posi: 419 [M + Na]⁺. MS ESI/APCI Dual nega: 395 [M − H]⁻. Example 1-196

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17 (s, 6 H) 2.12 (s, 3 H) 2.40-2.60 (m, 2 H) 3.45 (d, J = 4.2 Hz, 2 H) 3.75 (s, 3H) 4.53 (br. s., 2 H) 6.84 (d, J = 7.9 Hz, 1 H) 7.01- 7.12 (m, 2 H). MS ESI/APCI Dual posi: 399 [M + Na]⁺. MS ESI/APCI Dual nega: 375 [M − H]⁻. Na Example 1-197

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.73-0.80 (m, 3 H) 0.89-0.98 (m, 3 H) 1.97-2.14 (m, 1 H) 2.15-2.28 (m, 1 H) 3.17-3,29 (m, 1 H) 3.36-3.46 (m, 1 H) 4.12-4.27 (m, 2 H) 4.55-4.75 (m, 2 H) 7.37-7.44 (m, 2 H) 7.57-7.64 (m, 2 H) 10.11-10.61 (m, 1 H). MS ESI/APCI Dual posi: 415 [M + H]⁺. MS ESI/APCI Dual nega: 413 [M − H]⁻. Example 1-198

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.38 (m, 2 H) 0.58-0.69 (m, 2 H) 1.18-1.32 (m, 7 H) 2.48-2.62 (m, 2 H) 3.73-3.82 (m, 2 H) 4.12-4.23 (m, 2 H) 4.57-4.68 (m, 2 H) 6.80-6.89 (m, 2 H) 7.12-7.23 (m, 2 H) 10.24-10.41 (m, 1 H). MS ESI/APCI Dual posi: 403 [M + H]⁺. MS ESI/APCI Dual nega: 401 [M − H]⁻. Example 1-199

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.27-0.37 (m, 2 H) 0.49-0.60 (m, 2 H) 1.09-1.29 (m, 7 H) 2.14 (s, 3 H) 2.41-2.64 (m, 2 H) 3.45-3.53 (m, 2 H) 3.74-3.83 (m, 2 H) 4.52 (s, 2 H) 6.74-6.86 (m, 1 H) 6.96-7.10 (m, 2 H) 9.94-10.38 (m, 1 H). MS ESI/APCI Dual posi: 417 [M + H]⁺. MS ESI/APCI Dual nega: 415 [M − H]⁻. Na

TABLE 21-29 Compound Salt No. Structure Analytical Data information Example 1-200

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.65-0.77 (m, 2 H) 1.06-1.15 (m, 2 H) 3.23 (s, 2 H) 3.52-3.59 (m, 2 H) 4.61 (s, 2 H) 7.31-7.40 (m, 3 H) 7.41-7.51 (m, 2 H) 7.60-7.69 (m, 4 H) 10.27 (br. s., 1 H). MS ESI/APCI Dual posi: 407 [M + H]⁺. MS ESI/APCI Dual nega: 405 [M − H]⁻. Na Example 1-201

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22-1.34 (m, 6 H) 1.96-2.15 (m, 2 H) 2.23-2.45 (m, 2 H) 2.49-2.68 (m, 2 H) 3.98-4.11 (m, 2 H) 4.14-4.27 (m, 2 H) 4.52-4.66 (m, 2 H) 6.79-7.11 (m, 3 H) 10.17-10.45 (m, 1 H). MS ESI/APCI Dual posi: 477 [M + H]⁺. MS ESI/APCI Dual nega: 475 [M − H]⁻. Example 1-202

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21-1.33 (m, 6 H) 2.23-2.42 (m, 3 H) 2.45-2.68 (m, 2 H) 4.12-4.23 (m, 2 H) 4.54-4.67 (m, 2 H) 6.98-7.25 (m, 3 H) 10.17-10.44 (m, 1 H). MS ESI/APCI Dual posi: 381 [M + H]⁺, 403 [M + Na]⁺. MS ESI/APCI Dual nega: 379 [M − H]⁻. Example 1-203

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.55-0.74 (m, 2 H) 0.85-1.01 (m, 2 H) 1.21-1.33 (m, 6 H) 1.76-1.94 (m, 1 H) 2.45-2.66 (m, 2 H) 4.08-4.25 (m, 2 H) 4.54-4.73 (m, 2 H) 6.95-7.06 (m, 2 H) 7.09-7.20 (m, 2 H) 10.21-10.42 (m, 1 H). MS ESI/APCI Dual posi: 373 [M + H]⁺, 395 [M + Na]⁺. MS ESI/APCI Dual nega: 371 [M − H]⁻. Example 1-204

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.28-0.40 (m, 2 H) 0.57-0.70 (m, 2 H) 1.17-1.35 (m, 7 H) 2.50-2.64 (m, 2 H) 3.81-3.89 (m, 2 H) 4.10-4.23 (m, 2 H) 4.53-4.65 (m, 2 H) 6.80-7.10 (m, 3 H) 10.15-10.43 (m, 1 H). MS ESI/APCI Dual posi: 421 [M + H]⁺. MS ESI/APCI Dual nega: 419 [M − H]⁻. Example 1-205

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.53-2.68 (m, 2 H) 3.31-3.42 (m, 2 H) 4.15-4.22 (m, 2 H) 4.55-4.62 (m, 2 H) 6.88-7.08 (m, 6 H) 7.19-7.26 (m, 2 H) 10.17-10.44 (m, 1 H). MS ESI/APCI Dual posi: 415 [M + H]⁺, 437 [M + Na]⁺. MS ESI/APCI Dual nega: 413 [M − H]⁻. Example 1-206

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23-1.34 (m, 6 H) 2.35 (s, 3 H) 2.50-2.62 (m, 2 H) 4.13-4.22 (m, 2 H) 4.56-4.65 (m, 2 H) 6.80-6.90 (m, 1 H) 6.95-7.06 (m, 2 H) 7.17-7.22 (m, 2 H) 7.60-7.72 (m, 1 H) 8.08-8.17 (m, 1 H) 10.16-10.48 (m, 1 H). MS ESI/APCI Dual posi: 440 [M + H]⁺, 462 [M + Na]⁺. MS ESI/APCI Dual nega: 438 [M − H]⁻.

TABLE 21-30 Compound Salt No. Structure Analytical Data information Example 1-207

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.50-0.75 (m, 2 H) 1.23-1.45 (m, 2 H) 3.07-3.17 (m, 2 H) 4.14-4.23 (m, 2 H) 4.54-4.60 (m, 2 H) 7.10-7.19 (m, 2 H) 7.42-7.52 (m, 2 H) 10.17-10.56 (m, 1 H). MS ESI/APCI Dual posi: 411 [M + H]⁺. MS ESI/APCI Dual nega: 409 [M − H]⁻. Example 1-208

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.52-0.78 (m, 2 H) 1.27-1.47 (m, 2 H) 3.09-3.21 (m, 2 H) 4.15-4.24 (m, 2 H) 4.58-4.66 (m, 2 H) 7.11-7.40 (m, 4 H) 10.17- 10.63 (m, 1 H). MS ESI/APCI Dual posi: 415 [M + H]⁺. MS ESI/APCI Dual nega: 413 [M − H]⁻. Example 1-209

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.28 (s, 3 H) 2.62-2.77 (m, 2 H) 3.27-3.47 (m, 2 H) 3.95-4.10 (m, 2 H) 4.46-4.64 (m, 2 H) 6.85-7.00 (m, 4 H) 7.12-7.21 (m, 2 H) 7.24-7.34 (m, 2 H) 9.97-10.28 (m, 1 H) 12.85 (br. s., 1 H). MS ESI/APCI Dual posi: 411 [M + H]⁺, 433 [M + Na]⁺. MS ESI/APCI Dual nega: 409 [M − H]⁻. Example 1-210

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07-1.20 (m, 3 H) 1.20-1.41 (m, 2 H) 1.49-1.72 (m, 2 H) 2.23-2.40 (m, 1 H) 2.75-3.03 (m, 1 H) 3.83-4.00 (m, 1 H) 4.07-4.25 (m, 2 H) 7.37-7.49 (m, 2 H) 7.49-7.60 (m, 2 H) 10.03- 10.40 (m, 1 H). MS ESI/APCI Dual posi: 413 [M + H]⁺. MS ESI/APCI Dual nega: 411 [M − H]⁻. Example 1-211

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.23-1.31 (m, 6 H) 1.79-1.89 (m, 1 H) 1.95-2.06 (m, 1 H) 2.07-2.17 (m, 2 H) 2.26-2.37 (m, 2 H) 2.51-2.63 (m, 2 H) 3.46-3.56 (m, 1 H) 4.14-4.23 (m, 2 H) 4.60-4.70 (m, 2 H) 7.12-7.22 (m, 4 H) 10.25-10.41 (m, 1 H). MS ESI/APCI Dual posi: 387 [M + H]⁺, 409 [M + Na]⁺. MS ESI/APCI Dual nega: 358 [M − H]⁻. Example 1-212

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.70-0.80 (m, 2 H) 0.99-1.09 (m, 2 H) 2.13-2.24 (m, 1 H) 2.53-2.68 (m, 2 H) 3.29-3.39 (m, 2 H) 4.16-4.24 (m, 2 H) 4.55-4.64 (m, 2 H) 7.01 (d, J = 8.3 Hz, 1 H) 7.34 (d, J = 6.6 Hz, 1 H) 7.45-7.52 (m, 1 H) 10.06-10.54 (m, 1 H). MS ESI/APCI Dual posi: 413 [M + H]⁺. MS ESI/APCI Dual nega: 411 [M − H]⁻. Example 1-213

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.33-1.43 (m, 6 H) 2.51-2.71 (m, 2 H) 4.13-4.25 (m, 2 H) 4.67-4.81 (m, 2 H) 6.45-6.61 (m, 1 H) 7.36-7.48 (m, 2 H) 7.67-7.79 (m, 2 H) 9.95-10.55 (m, 1 H). MS ESI/APCI Dual posi: 434 [M + H]⁺, 456 [M + Na]⁺. MS ESI/APCI Dual nega: 432 [M − H]⁻.

TABLE 21-31 Compound Salt No. Structure Analytical Data information Example 1-214

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.49-1.02 (m, 6 H) 1.25-1.42 (m, 2 H) 1.82-1.94 (m, 1 H) 3.07- 3.16 (m, 2 H) 4.16-4.21 (m, 2 H) 4.55-4.61 (m, 2 H) 6.99-7.08 (m, 2 H) 7.10-7.19 (m, 2 H) 10.27-10.55 (m, 1 H). MS ESI/APCI Dual posi: 371 [M + H]⁺. MS ESI/APCI Dual nega: 369 [M − H]⁻. Example 1-215

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.51-0.76 (m, 2 H) 1.27-1.45 (m, 2 H) 3.09-3.17 (m, 2 H) 4.17-4.23 (m, 2 H) 4.56-4.63 (m, 2 H) 7.15-7.38 (m, 4 H) 10.20- 10.59 (m, 1 H). MS ESI/APCI Dual posi: 365 [M + H]⁺. MS ESI/APCI Dual nega: 363 [M − H]⁻. Example 1-216

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.30-1.43 (m, 6 H) 2.47-2.68 (m, 2 H) 4.04-4.29 (m, 2 H), 4.66-4.84 (m, 2 H) 6.46-6.65 (m, 1 H) 7.37-7.48 (m, 2 H) 7.62-7.77 (m, 2 H) 10.06-10.54 (m, 1 H). MS ESI/APCI Dual posi: 434 [M + H]⁺, 456 [M + Na]⁺. MS ESI/APCI Dual nega: 432 [M − H]⁻. Example 1-217

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.30-1.38 (m, 6 H) 2.21-2.31 (m, 4 H) 2.47-2.57 (m, 2 H) 2.57-2.69 (m, 1 H) 3.63-3.74 (m, 3 H) 4.14-4.21 (m, 2 H) 7.15-7.22 (m, 1 H) 7.22-7.27 (m, 2 H) 7.28-7.34 (m, 2 H) 10.33 (br. s., 1 H). MS ESI/APCI Dual posi: 387 [M + H]⁺, 409 [M + Na]⁺. MS ESI/APCI Dual nega: 385 [M − H]⁻. Example 1-218

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.29-1.36 (m, 6 H) 1.83-1.97 (m, 2 H) 2.45-2.58 (m, 5 H) 3.24-3.38 (m, 1 H) 3.39-3.49 (m, 2 H) 4.17 (dd, J = 10.1, 5.6 Hz, 2 H) 7.15-7.23 (m, 3 H) 7.27-7.33 (m, 2 H) 10.17-10.37 (m, 1 H). MS ESI/APCI Dual posi: 387 [M + H]⁺, 409 [M + Na]⁺. MS ESI/APCI Dual nega: 385 [M − H]⁻. Example 1-219

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.32-1.51 (m, 4 H) 2.53-2.76 (m, 2 H) 3.51-3.69 (m, 2 H) 4.04-4.24 (m, 2 H) 7.23-7.37 (m, 3 H) 7.38-7.47 (m, 2 H) 7.49-7.58 (m, 4 H) 10.11-10.46 (m, 1 H). MS ESI/APCI Dual posi: 407 [M + H]⁺. MS ESI/APCI Dual nega: 405 [M − H]⁻. Example 1-220

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 1.06-1.27 (m, 1 H) 1.35-2.11 (m, 8 H) 2.44-2.63 (m, 3 H) 2.73 (d, J = 8.1 Hz, 1 H) 3.30-3.54 (m, 2 H) 3.82-3.91 (m, 2 H) 4.22-4.45 (m, 1 H) 7.08-7.33 (m, 5 H). MS ESI/APCI Dual posi: 387 [M + H]⁺, 409 [M + Na]⁺. MS ESI/APCI Dual nega: 385 [M − H]⁻. Na

TABLE 21-32 Compound Salt No. Structure Analytical Data information Example 1-221

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.17-1.33 (m, 6 H) 2.47-2.65 (m, 2 H) 4.10-4.25 (m, 2 H) 4.25-4.40 (m, 2 H) 4.57-4.70 (m, 2 H) 6.85-6.94 (m, 2 H) 7.19-7.25 (m, 2 H) 10.21-10.44 (m, 1 H). MS ESI/APCI Dual posi: 431 [M + H]⁺, 453 [M + Na]⁺. MS ESI/APCI Dual nega: 429 [M − H]⁻. Example 1-222

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 2.51-2.66 (m, 2 H) 3.30-3.40 (m, 2 H) 3.89 (s, 2 H) 4.50-4.65 (m, 4 H) 7.07-7.16 (m, 1 H) 7.20-7.32 (m, 1 H) 7.34-7.44 (m, 1 H). MS ESI/APCI Dual posi: 437 [M + H]⁺, 459 [M + Na]⁺. Na Example 1-223

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.56-0.84 (m, 2 H) 0.84-1.04 (m, 2 H) 2.41-2.69 (m, 2 H) 3.97-4.13 (m, 2 H) 4.46-4.60 (m, 2 H) 7.31-7.42 (m, 3 H) 7.42-7.51 (m, 2 H) 7.58-7.69 (m, 4 H) 9.88-10.34 (m, 1 H) 12.89 (br. s., 1 H). MS ESI/APCI Dual posi: 407 [M + H]⁺. Example 1-224

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.57-0.77 (m, 2 H) 0.85-1.00 (m, 2 H) 2.40-2.64 (m, 2 H) 4.12-4.29 (m, 2 H) 4.57 (s, 2 H) 7.30-7.40 (m, 2 H) 7.55-7.63 (m, 2 H) 10.00-10.15 (m, 1 H). MS ESI/APCI Dual posi: 399 [M + H]⁺, 421 [M + Na]⁺. Example 1-225

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54-2.74 (m, 2 H) 3.31-3.46 (m, 2 H) 4.13-4.25 (m, 2 H) 4.54-4.65 (m, 2 H) 7.00 (d, J = 8.5 Hz, 1 H) 7.17-7.30 (m, 2 H) 7.62- 7.73 (m, 2 H) 7.79 (dd, J = 8.5, 2.5 Hz, 1 H) 8.16 (d, J = 2.5 Hz, 1 H) 10.11 (m, 1 H). MS ESI/APCI Dual posi: 423 [M + H]⁺. MS ESI/APCI Dual nega: 421 [M − H]⁻. HCl Example 1-226

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.58-2.72 (m, 2 H) 3.40 (t, J = 7.1 Hz, 2 H) 3.73 (d, J = 4.8 Hz, 2 H) 4.59 (s, 2 H) 7.11-7.20 (m, 2 H) 7.26 (t, J = 4.8 Hz, 1 H) 7.35 (d, J = 8.5 Hz, 2 H) 8.64 (d, J = 4.8 Hz, 2 H) 9.97-10.14 (m, 1 H). MS ESI/APCI Dual posi: 399 [M + H]⁺. MS ESI/APCI Dual nega: 397 [M − H]⁻. Na Example 1-227

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.98-1.07 (m, 3 H) 1.22-1.29 (m, 6 H) 1.71-1.88 (m, 2 H) 2.50-2.61 (m, 2 H) 3.85-3.94 (m, 2 H) 4.10-4.22 (m, 2 H) 4.58-4.66 (m, 2 H) 6.79-6.88 (m, 2 H) 7.13-7.23 (m, 2 H) 10.22-10.38 (m, 1 H). MS ESI/APCI Dual posi: 391 [M + H]⁺, 413 [M + Na]⁺. MS ESI/APCI Dual nega: 389 [M − H]⁻.

TABLE 21-33 Compound Salt No. Structure Analytical Data information Example 1-228

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23-1.29 (m, 6 H) 1.29-1.35 (m, 6 H) 2.51-2.62 (m, 2 H) 4.12-4.22 (m, 2 H) 4.44-4.57 (m, 1 H) 4.58-4.67 (m, 2 H) 6.76-6.88 (m, 2 H) 7.10-7.24 (m, 2 H) 10.23-10.40 (m, 1 H). MS ESI/APCI Dual posi: 391 [M + H]⁺, 413 [M + Na]⁺. MS ESI/APCI Dual nega: 389 [M − H]⁻. Example 1-229

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.86-1.07 (m, 2 H) 1.24-1.31 (m, 6 H) 1.29-1.37 (m, 1 H) 1.89-1.99 (m, 1 H) 2.43-2.54 (m, 2 H) 3.37-3.46 (m, 2 H) 3.46-3.53 (m, 2 H) 6.97-7.14 (m, 3 H) 7.16-7.27 (m, 2 H) 10.11 (br. s., 1 H). MS ESI/APCI Dual posi: 373 [M + H]⁺. MS ESI/APCI Dual nega: 371 [M − H]⁻. Example 1-230

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45-1.68 (m, 3 H) 2.41-2.62 (m, 2 H) 2.96-3.11 (m, 1 H) 3.21-3.37 (m, 1 H) 4.17-4.25 (m, 2 H) 5.84-6.13 (m, 1 H) 7.30-7.49 (m, 5 H) 7.52-7.64 (m, 4 H) 10.19-10.50 (m, 1 H). MS ESI/APCI Dual posi: 395 [M + H]⁺, 417 [M + Na]⁺. MS ESI/APCI Dual nega: 393 [M − H]⁻. Example 1-231

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.60-1.79 (m, 6 H) 2.55-2.79 (m, 2 H) 3.50-3.65 (m, 2 H) 3.96-4.16 (m, 2 H) 7.41 (d, J = 8.1 Hz, 2 H) 7.51-7.65 (m, 2 H) 9.77- 10.51 (m, 1 H). MS ESI/APCI Dual posi: 401 [M + H]⁺, 423 [M + Na]⁺. MS ESI/APCI Dual nega: 399 [M − H]⁻. Example 1-232

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.93 (s, 9 H) 2.47-2.68 (m, 2 H) 3.06-3.17 (m, 2 H) 3.27-3.43 (m, 2 H) 4.15-4.25 (m, 2 H) 4.51 (s, 2 H) 4.56-4.66 (m, 2 H) 7.21-7.27 (m, 2 H) 7.28-7.35 (m, 2 H) 10.19-10.46 (m, 1 H). MS ESI/APCI Dual posi: 405 [M + H]⁺, 427 [M + Na]⁺. MS ESI/APCI Dual nega: 403 [M − H]⁻. Example 1-233

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 0.27-0.34 (m, 2 H) 0.35-0.42 (m, 2 H) 1.13 (s, 3 H) 2.50-2.61 (m, 2 H) 3.23-3.27 (m, 2 H) 3.33-3.38 (m, 2 H) 3.89 (s, 2 H) 4.49 (s, 2 H) 4.62 (s, 2 H) 7.24-7.35 (m, 4 H). MS ESI/APCI Dual posi: 403 [M + H]⁺, 425 [M + Na]⁺. MS ESI/APCI Dual nega: 401 [M − H]⁻. Na Example 1-234

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20-1.29 (m, 6 H) 1.35-1.44 (m, 3 H) 2.47-2.63 (m, 2 H) 3.96-4.06 (m, 2 H) 4.13-4.23 (m, 2 H) 4.58-4.67 (m, 2 H) 6.78-6.88 (m, 2 H) 7.12-7.24 (m, 2 H) 10.24-10.38 (m, 1 H). MS ESI/APCI Dual posi: 377 [M + H]⁺. MS ESI/APCI Dual nega: 375 [M − H]⁻.

TABLE 21-34 Compound Salt No. Structure Analytical Data information Example 1-235

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.30-0.38 (m, 2 H) 0.58-0.70 (m, 2 H) 1.16-1.35 (m, 1 H) 2.49-2.64 (m, 2 H) 3.25-3.37 (m, 2 H) 3.74-3.82 (m, 2 H) 4.14-4.22 (m, 2 H) 4.50-4.59 (m, 2 H) 6.81-6.91 (m, 2 H) 7.15-7.21 (m, 2 H) 10.16-10.42 (m, 1 H). MS ESI/APCI Dual posi: 375 [M + H]⁺. MS ESI/APCI Dual nega: 373 [M − H]⁻. Example 1-236

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.60-0.71 (m, 2 H) 0.85-1.01 (m, 2 H) 1.62-2.02 (m, 5 H) 2.27-2.49 (m, 2 H) 2.77-2.92 (m, 2 H) 4.10-4.22 (m, 2 H) 4.74-4.86 (m, 2 H) 6.96-7.07 (m, 2 H) 7.07-7.16 (m, 2 H) 10.12-10.40 (m, 1 H). MS ESI/APCI Dual posi: 385 [M + H]⁺. MS ESI/APCI Dual nega: 383 [M − H]⁻. Example 1-237

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.64-0.72 (m, 2 H) 0.91-1.02 (m, 2 H) 1.51-2.02 (m, 5 H) 2.34-2.54 (m, 2 H) 3.27-3.34 (m, 2 H) 4.15-4.23 (m, 2 H) 4.55-4.60 (m, 2 H) 7.00-7.09 (m, 2 H) 7.12-7.20 (m, 2 H) 10.29-10.58 (m, 1 H). MS ESI/APCI Dual posi: 385 [M + H]⁺. MS ESI/APCI Dual nega: 383 [M − H]⁻. Example 1-238

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.77-2.22 (m, 6 H) 2.47-2.66 (m, 2 H) 2.69-2.84 (m, 1 H) 3.26-3.38 (m, 2 H) 3.86-3.96 (m, 2 H) 4.15-4.22 (m, 2 H) 4.56 (s, 2 H) 6.83-6.92 (m, 2 H) 7.13-7.23 (m, 2 H) 10.18-10.43 (m, 1 H). MS ESI/APCI Dual posi: 389 [M + H]⁺. MS ESI/APCI Dual nega: 387 [M − H]⁻. Example 1-239

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22-1.29 (m, 6 H) 1.76-2.03 (m, 4 H) 2.04-2.21 (m, 2 H) 2.47-2.62 (m, 2 H) 2.68-2.83 (m, 1 H) 3.86-3.93 (m, 2 H) 4.13-4.23 (m, 2 H) 4.53-4.68 (m, 2 H) 6.78-6.90 (m, 2 H) 7.12-7.24 (m, 2 H) 10.27-10.42 (m, 1 H). MS ESI/APCI Dual posi: 417 [M + H]⁺. MS ESI/APCI Dual nega: 415 [M − H]⁻. Example 1-240

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.46-2.68 (m, 2 H) 3.24-3.40 (m, 2 H) 4.09-4.26 (m, 2H) 4.49-4.63 (m, 2 H) 5.05 (s, 2 H) 6.90-6.98 (m, 2 H) 7.15-7.23 (m, 2 H) 7.28-7.46 (m, 5 H) 10.21-10.45 (m, 1 H). MS ESI/APCI Dual posi: 411 [M + H]⁺, 433 [M + Na]⁺. MS ESI/APCI Dual nega: 409 [M − H]⁻. Example 1-241

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.40-2.69 (m, 2 H) 3.23-3.40 (m, 2 H) 3.93-4.07 (m, 2 H) 4.43-4.58 (m, 2 H) 5.06 (s, 2 H) 6.89-7.04 (m, 2 H) 7.14-7.29 (m, 4 H) 7.42- 7.56 (m, 2 H) 100-10.26 (m, 1 H). MS ESI/APCI Dual posi: 429 [M + H]⁺, 451 [M + Na]⁺. MS ESI/APCI Dual nega: 427 [M − H]⁻.

TABLE 21-35 Compound Salt No. Structure Analytical Data information Example 1-242

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.49-2.68 (m, 2 H) 3.25-3.40 (m, 2 H) 4.12-4.24 (m, 2 H) 4.50-4.60 (m, 2 H) 4.97-5.06 (m, 2 H) 6.88-6.96 (m, 2 H) 7.15-7.23 (m, 2 H) 7.36 (s, 4 H) 10.21-10.44 (m, 1 H). MS ESI/APCI Dual posi: 445 [M + H]⁺, 467 [M + Na]⁺. MS ESI/APCI Dual nega: 443 [M − H]⁻. Example 1-243

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.74-2.45 (m, 6 H) 2.64 (t, J = 7.1 Hz, 2 H) 3.34 (t, J = 7.1 Hz, 2 H) 3.77-3.98 (m, 1 H) 4.14-4.27 (m, 2 H) 4.56-4.68 (m, 2 H) 7.37-7.50 (m, 2 H) 7.50-7.64 (m, 1 H) 10.06-10.55 (m, 1 H). MS ESI/APCI Dual posi: 427 [M + H]⁺. MS ESI/APCI Dual nega: 425 [M − H]⁻. Example 1-244

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.92-1.26 (m, 8 H) 1.27-1.46 (m, 1 H) 2.13-2.28 (m, 1 H) 2.30-2.49 (m, 2 H) 2.83-3.00 (m, 1 H) 3.08-3.25 (m, 1 H) 3.54 (d, J = 4.4 Hz, 2 H) 7.13-7.41 (m, 5 H) 10.15 (br. s., 1 H). MS ESI/APCI Dual posi: 373 [M + H]⁺. MS ESI/APCI Dual nega: 371 [M − H]⁻. Na Example 1-245

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.69-2.37 (m, 6 H) 2.48-2.53 (m, 2 H) 3.32 (t, J = 6.9 Hz, 2 H) 3.54 (d, J = 4.4 Hz, 2 H) 3.78 (quin, J = 8.5 Hz, 1 H) 4.59-4.74 (m, 2 H) 7.27 (d, J = 8.1 Hz, 1 H) 7.46-7.75 (m, 2 H) 10.11 (br. s., 1 H). MS ESI/APCI Dual posi: 427 [M + H]⁺. MS ESI/APCI Dual nega: 425 [M − H]⁻. Na Example 1-246

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.06-0.16 (m, 2 H) 0.37-0.47 (m, 2 H) 0.74-0.92 (m, 1 H) 1.55-1.67 (m, 2 H) 2.43-2.55 (m, 2 H) 3.20-3.31 (m, 2 H) 3.49-3.57 (m, 2 H) 3.93-4.05 (m, 2 H) 4.48 (s, 2 H) 6.83-6.94 (m, 2 H) 7.11- 7.25 (m, 2 H) 10.11 (br. s., 1 H). MS ESI/APCI Dual posi: 389 [M + H]⁺. MS ESI/APCI Dual nega: 387 [M − H]⁻. Na Example 1-247

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.06-0.15 (m, 2 H) 0.36-0.48 (m, 2 H) 0.73-0.91 (m, 1 H) 1.16 (s, 6 H) 1.52-1.67 (m, 2 H) 2.43-2.59 (m, 2 H) 3.43-3.54 (m, 2 H) 3.92-4.03 (m, 2 H) 4.56 (s, 2 H) 6.79-6.93 (m, 2 H) 7.14- 7.27 (m, 2 H) 9.95-10.26 (m, 1 H). MS ESI/APCI Dual posi: 417 [M + H]⁺. MS ESI/APCI Dual nega: 415 [M − H]⁻. Na Example 1-248

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 1.06-1.26 (m, 2 H) 1.61-1.75 (m, 2 H) 1.81-2.00 (m, 1 H) 2.61 (t, J = 7.2 Hz, 2 H) 2.72-2.94 (m, 2 H) 3.30-3.34 (m, 2 H) 3.45 (t, J = 7.1 Hz, 2 H) 3.94 (s, 2 H) 4.08-4.21 (m, 2 H) 5.10 (s, 2 H) 7.24-7.38 (m, 5 H). MS ESI/APCI Dual posi: 446 [M + H]⁺, 468 [M + Na]⁺. MS ESI/APCI Dual nega: 444 [M − H]⁻. Na

TABLE 21-36 Compound Salt No. Structure Analytical Data information Example 1-249

¹H NMR (300 MHz, METHANOL-d₄) δ ppm −0.02-0.06 (m, 2 H) 0.38-0.44 (m, 2 H) 0.59-0.79 (m, 1 H) 1.39-1.54 (m, 2 H) 2.55 (t, J = 7.2 Hz, 2 H) 2.62-2.74 (m, 2 H) 3.31-3.35 (m, 2 H) 3.89 (s, 2 H) 4.58 (s, 2 H) 7.11-7.24 (m, 4 H). MS ESI/APCI Dual posi: 373 [M + H]⁺. MS ESI/APCI Dual nega: 371 [M − H]⁻. Na Example 1-250

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.26-0.36 (m, 2 H) 0.48-0.61 (m, 2 H) 1.11-1.32 (m, 1 H) 1.48-1.95 (m, 4 H) 2.18-2.34 (m, 2 H) 3.32 (s, 2 H) 3.47-3.55 (m, 2 H) 3.73-3.82 (m, 2 H) 4.50 (s, 2 H) 6.89 (d, J = 8.7 Hz, 2 H) 7.21 (d, J = 8.7 Hz, 2 H). MS ESI/APCI Dual posi: 415 [M + H]⁺. MS ESI/APCI Dual nega: 413 [M − H]⁻. Na Example 1-251

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.27-0.34 (m, 2 H) 0.51-0.63 (m, 4 H) 0.81-0.92 (m, 2 H) 1.12-1.27 (m, 1 H) 2.39-2.58 (m, 2 H) 3.42-3.49 (m, 2 H) 3.73- 3.81 (m, 2 H) 4.39 (s, 2 H) 6.81-6.88 (m, 2 H) 7.12-7.20 (m, 2 H). MS ESI/APCI Dual posi: 401 [M + H]⁺. MS ESI/APCI Dual nega: 399 [M − H]⁻. Example 1-252

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.59-2.74 (m, 2 H) 3.41 (t, J = 7.1 Hz, 2 H) 4.02 (d, J = 5.8 Hz, 2 H) 4.54 (s, 2 H) 7.02 (d, J = 8.5 Hz, 1 H) 7.12-7.30 (m, 4 H) 7.78 (dd, J = 8.5, 2.3 Hz, 1 H) 8.09 (d, J = 2.3 Hz, 1 H) 10.00 (br. s., 1 H). MS ESI/APCI Dual posi: 416 [M + H]⁺. MS ESI/APCI Dual nega: 414 [M − H]⁻. HCl Example 1-253

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.95-1.81 (m, 10 H) 2.69-2.83 (m, 2 H) 4.09-4.24 (m, 2 H) 4.70-4.82 (m, 2 H) 7.14-7.38 (m, 5 H) 10.17-10.38 (m, 1 H). MS ESI/APCI Dual posi: 373 [M + H]⁺, 395 [M + Na]⁺. MS ESI/APCI Dual nega: 371 [M − H]⁻. Example 1-254

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.36-2.48 (m, 2 H) 3.20-3.37 (m, 2 H) 3.51 (d, J = 4.4 Hz, 2 H) 4.53 (s, 2 H) 7.11 (d, J = 8.4 Hz, 1 H) 7.33 (d, J = 8.5 Hz, 2 H) 7.67- 7.90 (m, 3 H) 8.13 (d, J = 2.2 Hz, 1 H) 10.11 (br. s., 1 H). MS ESI/APCI Dual posi: 466 [M + H]⁺. MS ESI/APCI Dual nega: 464 [M − H]⁻. Na Example 1-255

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 2.60- 2.78 (m, 2 H) 3.42 (t, J = 7.1 Hz, 2 H) 4.02 (d, J = 5.6 Hz, 2 H) 4.54 (s, 2 H) 6.77-7.07 (m, 4 H) 7.19-7.35 (m, 1 H) 7.77 (dd, J = 8.5, 2.5 Hz, 1 H) 8.11 (d, J = 2.5 Hz, 1 H) 10.00 (br. s., 1 H). MS ESI/APCI Dual posi: 412 [M + H]⁺. MS ESI/APCI Dual nega: 410 [M − H]⁻. HCl

TABLE 21-37 Compound Salt No. Structure Analytical Data information Example 1-256

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.41-2.63 (m, 2 H) 3.34 (t, J = 7.1 Hz, 2 H) 3.49 (d, J = 4.4 Hz, 2 H) 4.53 (s, 2 H) 6.89-7.13 (m, 4 H) 7.34-7.54 (m, 1 H) 7.80 (dd, J = 8.5, 2.4 Hz, 1 H) 8.12 (d, J = 2.4 Hz, 1 H) 10.05 (br. s., 1 H). MS ESI/APCI Dual posi: 416 [M + H]⁺. MS ESI/APCI Dual nega: 414 [M − H]⁻. Na Example 1-257

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.28 (s, 3 H) 2.53-2.56 (m, 2 H) 3.31 (t, J = 6.9 Hz, 2 H) 3.50 (d, J = 4.4 Hz, 2 H) 4.54 (s, 2 H) 6.70-6.85 (m, 2 H) 6.88-7.02 (m, 3 H) 7.17-7.36 (m, 3 H) 10.09 (br. s., 1 H). MS ESI/APCI Dual posi: 411 [M + H]⁺. MS ESI/APCI Dual nega: 409 [M − H]⁻. Na Example 1-258

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50-2.57 (m, 2 H) 3.25-3.35 (m, 2 H) 3.47 (d, J = 4.5 Hz, 2 H) 4.56 (s, 2 H) 6.77- 7.00 (m, 3 H) 7.01-7.07 (m, 2 H) 7.27-7.47 (m, 3 H) 10.08 (br. s., 1 H). MS ESI/APCI Dual posi: 415 [M + H]⁺. MS ESI/APCI Dual nega: 413 [M − H]⁻. Na Example 1-259

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50-2.57 (m, 2 H) 3.36-3.54 (m, 4 H) 4.63 (s, 2 H) 7.07-7.16 (m, 2 H) 7.20-7.43 (m, 4 H) 8.30 (d, J = 2.8 Hz, 1 H) 10.04 (br. s., 1 H). MS ESI/APCI Dual posi: 416 [M + H]⁺. MS ESI/APCI Dual nega: 414 [M − H]⁻. Na Example 1-260

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.29 (s, 3 H) 2.54-2.57 (m, 2 H) 3.28-3.49 (m, 4 H) 4.62 (s, 2 H) 6.88-7.01 (m, 2 H) 7.21 (dd, J = 8.7, 0.6 Hz, 2 H) 7.24-7.39 (m, 2 H) 8.27 (d, J = 2.8 Hz, 1 H) 10.03 (br. s., 1 H). MS ESI/APCI Dual posi: 412 [M + H]⁺. MS ESI/APCI Dual nega: 410 [M − H]⁻. Na Example 1-261

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.47-2.54 (m, 2 H) 3.27-3.35 (m, 2 H) 3.42 (d, J = 4.2 Hz, 2 H) 4.51 (s, 2 H) 7.05 (d, J = 8.2 Hz, 1 H) 7.50-7.63 (m, 5 H) 8.32-8.39 (m, 1 H). MS ESI/APCI Dual posi: 448 [M + H]⁺. MS ESI/APCI Dual nega: 446 [M − H]⁻. Na Example 1-262

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.52-1.82 (m, 2 H) 1.90-2.11 (m, 2 H) 2.34-2.50 (m, 4 H) 3.17- 3.47 (m, 4 H) 4.47 (s, 2 H) 4.58-4.73 (m, 1 H) 6.71- 6.84 (m, 2 H) 7.10-7.25 (m, 2 H). MS ESI/APCI Dual posi: 375 [M + H]⁺. MS ESI/APCI Dual nega: 373 [M − H]⁻. Na

TABLE 21-38 Compound Salt No. Structure Analytical Data information Example 1-263

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.93 (s, 3 H) 2.03 (s, 3 H) 2.49-2.52 (m, 2 H) 3.29-3.36 (m, 2 H) 3.45 (d, J = 4.2 Hz, 2 H) 4.45 (s, 2 H) 7.23-7.45 (m, 4 H) 7.57 (s, 1 H). MS ESI/APCI Dual posi: 399 [M + H]⁺. MS ESI/APCI Dual nega: 397 [M − H]⁻. Na Example 1-264

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 0.62-0.71 (m, 2 H) 0.71-0.81 (m, 2 H) 2.55 (t, J = 7.3 Hz, 2 H) 3.31-3.35 (m, 2 H) 3.72-3.80 (m, 1 H) 3.89 (s, 2 H) 4.55 (s, 2 H) 6.95-7.06 (m, 2 H) 7.17-7.28 (m, 2 H). MS ESI/APCI Dual posi: 361 [M + H]⁺. MS ESI/APCI Dual nega: 359 [M − H]⁻. Na Example 1-265

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.53-2.57 (m, 2 H) 3.31 (t, J = 7.1 Hz, 2 H) 3.50 (d, J = 4.5 Hz, 2 H) 4.55 (s, 2 H) 6.96-7.06 (m, 4 H) 7.27-7.34 (m, 2 H) 7.37-7.45 (m, 2 H) 10.09 (br. s., 1 H). MS ESI/APCI Dual posi: 431 [M + H]⁺. MS ESI/APCI Dual nega: 429 [M − H]⁻. Na Example 1-266

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.53-0.70 (m, 4 H) 0.80-0.98 (m, 4 H) 1.81-1.94 (m, 1 H) 2.38-2.47 (m, 2 H) 3.42-3.50 (m, 2 H) 4.41 (s, 2 H) 6.95-7.06 (m, 2 H) 7.08-7.17 (m, 2 H). MS ESI/APCI Dual posi: 371 [M + H]⁺. MS ESI/APCI Dual nega: 369 [M − H]⁻. Na Example 1-267

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.25-0.34 (m, 2 H) 0.48-0.60 (m, 2 H) 1.12-1.29 (m, 1 H) 1.53-1.86 (m, 4 H) 2.21-2.39 (m, 2 H) 2.72-2.82 (m, 2 H) 3.38- 3.47 (m, 2 H) 3.77 (d, J = 7.0 Hz, 2 H) 4.73 (s, 2 H) 6.85 (d, J = 8.9 Hz, 2 H) 7.17 (d, J = 8.9 Hz, 2 H). MS ESI/APCI Dual posi: 415 [M + H]⁺. MS ESI/APCI Dual nega: 413 [M − H]⁻. Na Example 1-268

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 2.49-2.51 (m, 2 H) 3.31-3.37 (m, 2 H) 3.46 (d, J = 4.5 Hz, 2 H) 4.44 (s, 2 H) 7.39-7.45 (m, 1 H) 7.48-7.53 (m, 4 H) 7.59 (s, 1 H). MS ESI/APCI Dual posi: 385 [M + H]⁺. MS ESI/APCI Dual nega: 383 [M − H]⁻. Na Example 1-269

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 2.05 (quin, J = 7.5 Hz, 2 H) 2.45-2.60 (m, 2 H) 2.84- 2.92 (m, 4 H) 3.30-3.31 (m, 2 H) 3.89 (s, 2 H) 4.57 (s, 2 H) 6.98-7.08 (m, 1 H) 7.10-7.21 (m, 2 H). MS ESI/APCI Dual posi: 345 [M + H]⁺. MS ESI/APCI Dual nega: 343 [M − H]⁻. Na

TABLE 21-39 Compound Salt No. Structure Analytical Data information Example 1-270

¹H NMR (300 MHz, METHANOL-d₆) δ ppm 2.43-2.63 (m, 2 H) 3.32-3.40 (m, 2 H) 3.90 (s, 2 H) 4.74 (s, 2 H) 7.27-7.37 (m, 2 H) 7.52-7.58 (m, 1 H) 7.75-7.79 (m, 1 H) 7.82- 7.99 (m, 1 H). MS ESI/APCI Dual posi: 361[M + H]⁺. MS ESI/APCI Dual nega: 359[M − H]⁻. Na Example 1-271

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.47-1.76 (m, 6 H) 1.80- 1.98 (m, 2 H) 2.44-2.51 (m, 2 H) 3.20-3.31 (m, 2 H) 3.46- 3.54 (m, 2 H) 4.47 (s, 2 H) 4.71-4.83 (m, 1 H) 6.80- 6.89 (m, 2 H) 7.11-7.23 (m, 2 H) 10.11 (br. s., 1 H). MS ESI/APCI Dual posi: 389[M + H]⁺. MS ESI/APCI Dual nega: 387[M − H]⁻. Na Example 1-272

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17 (s, 6 H) 1.48-1.76 (m, 6 H) 1.80-1.97 (m, 2 H) 2.43-2.62 (m, 2 H) 3.43- 3.52 (m, 2 H) 4.55 (s, 2 H) 4.72-4.80 (m, 1 H) 6.77-6.88 (m, 2 H) 7.14-7.23 (m, 2 H). MS ESI/APCI Dual posi: 417[M + H]⁺. MS ESI/APCI Dual nega: 415[M − H]⁻. Na Example 1-273

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.45 (s, 3 H) 2.56-2.71 (m, 2 H) 3.31-3.50 (m, 2 H) 3.95 (d, J = 5.4 Hz, 2 H) 4.56 (s, 2 H) 6.99 (d, J = 8.7 Hz, 2 H) 7.19-7.41 (m, 4 H) 8.24 (d, J = 2.8 Hz, 1 H) 10.08 (br. s., 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺. MS ESI/APCI Dual nega: 410[M − H]⁻. Na Example 1-274

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50-2.59 (m, 2 H) 3.27- 3.38 (m, 2 H) 3.48 (d, J = 4.5 Hz, 2 H) 4.51 (s, 2 H) 7.10 (dd, J = 8.5, 0.6 Hz, 1 H) 7.18-7.42 (m, 4 H) 7.79 (dd, J = 8.5, 2.5 Hz, 1 H) 8.03 (d, J = 2.5 Hz, 1 H) 10.03 (br. s., 1 H). MS ESI/APCI Dual posi: 416[M + H]⁺. MS ESI/APCI Dual nega: 414[M − H]⁻. Na Example 1-275

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.08 (s, 3 H) 2.53-2.59 (m, 2 H) 3.28-3.38 (m, 2 H) 3.51 (d, J = 4.5 Hz, 2 H) 4.51 (s, 2 H) 6.99 (dd, J = 16.6, 8.5 Hz, 2 H) 7.08-7.38 (m, 3 H) 7.75 (dd, J = 8.5, 2.4 Hz, 1 H) 8.04 (d, J = 2.4 Hz, 1 H) 10.08 (br. s., 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺. MS ESI/APCI Dual nega: 410[M − H]⁻. Na Example 1-276

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.05 (s, 6 H) 2.31 (s, 3 H) 3.10 (s, 2 H) 3.41-3.48 (m, 2 H) 4.52 (s, 2 H) 6.80-7.05 (m, 3 H) 7.20 (d, J = 8.1 Hz, 2 H) 7.77 (dd, J = 8.4, 2.6 Hz, 1 H) 8.09 (d, J = 2.6 Hz, 1 H). MS ESI/APCI Dual posi: 440[M + H]⁺. MS ESI/APCI Dual nega: 438[M − H]⁻. Na

TABLE 21-40 Compound Salt No. Structure Analytical Data information Example 1-277

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.58-0.78 (m, 2 H) 0.99- 1.15 (m, 2 H) 2.31 (s, 3 H) 3.20 (s, 2 H) 3.49 (s, 2 H) 4.51 (s, 2 H) 6.87-7.06 (m, 3 H) 7.20 (d, J = 8.2 Hz, 2 H) 7.73 (dd, J = 8.6, 2.4 Hz, 1 H) 8.05 (d, J = 2.4 Hz, 1 H) 10.08- 10.35 (m, 1 H). MS ESI/APCI Dual posi: 438[M + H]⁺. MS ESI/APCI Dual nega: 436[M − H]⁻. Na Example 1-278

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.46-1.64 (m, 2 H) 1.69- 1.97 (m, 2 H) 2.14-2.38 (m, 5 H) 3.20-3.40 (m, 2 H) 3.42- 3.53 (m, 2 H) 4.53 (s, 2 H) 6.89-7.03 (m, 3 H) 7.14- 7.25 (m, 2 H) 7.76 (dd, J = 8.4, 2.2 Hz, 1 H) 8.10 (d, J = 2.2 Hz, 1 H) 10.13-10.33 (m, 1 H). MS ESI/APCI Dual posi: 452[M + H]⁺. MS ESI/APCI Dual nega: 450[M − H]⁻. Na Example 1-279

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.24-0.36 (m, 2 H) 0.49- 0.75 (m, 4 H) 1.02-1.12 (m, 2 H) 1.13-1.29 (m, 1 H) 3.13 (s, 2 H) 3.51 (d, J = 4.5 Hz, 2 H) 3.78 (d, J = 7.0 Hz, 2 H) 4.48 (s, 2 H) 6.81-6.93 (m, 2 H) 7.12-7.23 (m, 2 H) 10.12-10.34 (m, 1 H). MS ESI/APCI Dual posi: 401[M + H]⁺. MS ESI/APCI Dual nega: 399[M − H]⁻. Na Example 1-280

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.59-1.90 (m, 4 H) 2.19- 2.37 (m, 5 H) 2.70 (s, 2 H) 3.46 (d, J = 4.2 Hz, 2 H) 4.76 (s, 2 H) 6.85-7.04 (m, 3 H) 7.15-7.24 (m, 2 H) 7.71 (dd, J = 8.4, 2.5 Hz, 1 H) 8.05 (d, J = 2.5 Hz, 1 H) 9.93-10.07 (m, 1 H). MS ESI/APCI Dual posi: 452[M + H]⁺. MS ESI/APCI Dual nega: 450[M − H]⁻. Example 1-281

¹H NMR (300 MHz, METHANOL-d₆) δ ppm 1.37 (s, 6 H) 2.64 (s, 2 H) 3.89 (s, 2 H) 4.82 (s, 2 H) 7.38 (s, 1 H) 7.41-7.50 (m, 3 H) 7.88-7.98 (m, 2 H). MS ESI/APCI Dual posi: 416[M + H]⁺. MS ESI/APCI Dual nega: 414[M − H]⁻. Na Example 1-282

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.53-2.58 (m, 2 H) 3.30 (t, J = 7.1 Hz, 2 H) 3.51 (d, J = 4.5 Hz, 2 H) 4.53 (s, 2 H) 6.90-6.98 (m, 2 H) 7.11-7.32 (m, 5 H) 7.33-7.43 (m, 1 H) 10.09 (br. s., 1 H). MS ESI/APCI Dual posi: 415[M + H]⁺. MS ESI/APCI Dual nega: 413[M − H]⁻. Na Example 1-283

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.17 (s, 3 H) 2.53-2.57 (m, 2 H) 3.26-3.34 (m, 2 H) 3.50 (d, J = 4.4 Hz, 2 H) 4.52 (s, 2 H) 6.81-6.93 (m, 3 H) 7.05-7.13 (m, 1 H) 7.16- 7.34 (m, 4 H) 10.09 (br. s., 1 H). MS ESI/APCI Dual posi: 411[M + H]⁺. MS ESI/APCI Dual nega: 409[M − H]⁻. Na

TABLE 21-41 Compound Salt No. Structure Analytical Data information Example 1-284

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.53-2.60 (m, 2 H) 3.35 (t, J = 6.9 Hz, 2 H) 3.51 (d, J = 4.5 Hz, 2 H) 4.53 (s, 2 H) 6.98-7.17 (m, 2 H) 7.23-7.32 (m, 2 H) 7.36-7.50 (m, 1 H) 7.80 (dd, J = 8.4, 2.4 Hz, 1 H) 8.07-8.17 (m, 1 H) 10.07 (br. s., 1 H). MS ESI/APCI Dual posi: 432[M + H]⁺. MS ESI/APCI Dual nega: 430[M − H]⁻. Na Example 1-285

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.54-2.64 (m, 2 H) 3.37 (t, J = 7.1 Hz, 2 H) 3.63 (d, J = 4.8 Hz, 2 H) 4.54 (s, 2 H) 7.11 (dd, J = 8.4, 0.6 Hz, 1 H) 7.38-7.71 (m, 4 H) 7.76- 7.89 (m, 1 H) 8.11 (d, J = 1.9 Hz, 1 H) 10.06 (br. s., 1 H). MS ESI/APCI Dual posi: 466[M + H]⁺. MS ESI/APCI Dual nega: 464[M − H]⁻. Na Example 1-286

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.40-2.50 (m, 2 H) 3.29 (t, J = 7.1 Hz, 2 H) 3.49 (d, J = 4.5 Hz, 2 H) 3.73 (s, 3 H) 4.54 (s, 2 H) 6.44-6.61 (m, 2 H) 6.70 (ddd, J = 8.3, 2.4, 0.9 Hz, 1 H) 6.91-7.05 (m, 2 H) 7.18-7.34 (m, 3 H) 10.10 (br. s., 1 H). MS ESI/APCI Dual posi: 427[M + H]⁺. MS ESI/APCI Dual nega: 425[M − H]⁻. Na Example 1-287

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50-2.57 (m, 2 H) 3.34 (t, J = 7.1 Haz, 2 H) 3.51 (d, J = 4.5 Hz, 2 H) 4.54 (s, 2 H) 7.07 (d, J = 0.6 Hz, 1 H) 7.14-7.28 (m, 3 H) 7.46-7.60 (m, 1 H), 7.81 (dd, J = 8.4, 2.5 Hz, 1 H) 8.12 (d, J = 1.9 Hz, 1 H) 10.07 (br. s., 1 H). MS ESI/APCI Dual posi: 482[M + H]⁺. MS ESI/APCI Dual nega: 480[M − H]⁻. Na Example 1-288

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50-2.58 (m, 2 H) 3.33 (t, J = 7.1 Hz, 2 H) 3.49 (d, J = 4.5 Hz, 2 H) 4.56 (s, 2 H) 7.02-7.16 (m, 3 H) 7.27-7.36 (m, 2 H) 7.75-7.88 (m, 1 H) 8.11-8.18 (m, 1 H) 10.09 (br. s., 1 H). MS ESI/APCI Dual posi: 416[M + H]⁺. MS ESI/APCI Dual nega: 414[M − H]⁻. Na Example 1-289

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.60-2.76 (m, 2 H) 3.42 (t, J = 7.1 Hz, 2 H) 4.02 (d, J = 5.8 Hz, 2 H) 4.59 (s, 2 H) 7.03-7.18 (m, 3 H) 7.28-7.38 (m, 2 H) 7.95 (dd, J = 8.8, 2.8 Hz, 1 H) 8.19 (dd, J = 2.8, 0.6 Hz, 1 H) 10.07 (br. s., 1 H). MS ESI/APCI Dual posi: 432[M + H]⁺. MS ESI/APCI Dual nega: 430[M − H]⁻. HCl Example 1-290

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50-2.59 (m, 2 H) 3.36 (t, J = 7.1 Hz, 2 H) 3.50 (d, J = 4.5 Hz, 2 H) 4.57 (s, 2 H) 6.86 (dd, J = 8.1, 1.1 Hz, 1 H) 6.94-7.07 (m, 2 H) 7.10- 7.37 (m, 5 H) 10.04 (br. s., 1 H). MS ESI/APCI Dual posi: 415[M + H]⁺. MS ESI/APCI Dual nega: 413[M − H]⁻. Na

TABLE 21-42 Compound Salt No. Structure Analytical Data information Example 1-291

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.44-2.56 (m, 2 H) 3.20- 3.31 (m, 2 H) 3.46-3.53 (m, 2 H) 4.51 (s, 2 H) 4.65-4.80 (m, 2 H) 6.96-7.07 (m, 2 H) 7.19-7.30 (m, 2 H) 9.94- 10.24 (m, 1 H). MS ESI/APCI Dual posi: 403[M + H]⁺. MS ESI/APCI Dual nega: 401[M − H]⁻. Na Example 1-292

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.50-2.59 (m, 2 H) 3.25- 3.35 (m, 2 H) 3.45-3.53 (m, 2 H) 4.50 (s, 2 H) 4.75-4.88 (m, 2 H) 7.04-7.30 (m, 3 H) 9.93-10.19 (m, 1 H). MS ESI/APCI Dual posi: 421[M + H]⁺. MS ESI/APCI Dual nega: 419[M − H]⁻. Na Example 1-293

¹H NMR (300 MHz, METHANOL-d₆) δ ppm 1.38 (s, 6 H) 2.65 (s, 2 H) 4.06 (s, 2 H) 4.69 (s, 2 H) 7.15 (s, 1 H) 7.38-7.54 (m, 3 H) 7.79-7.89 (m, 2 H). MS ESI/APCI Dual posi: 399[M + H]⁺. MS ESI/APCI Dual nega: 397[M − H]⁻. Example 1-294

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.29 (s, 6 H) 2.54-2.65 (m, 2 H) 3.49 (d, J = 4.5 Hz, 2 H) 4.90 (s, 2 H) 7.29-7.38 (m, 1 H) 7.39-7.49 (m, 2 H) 7.90-7.98 (m, 2 H) 8.00 (s, 1 H) 9.89-10.12 (m, 1 H). MS ESI/APCI Dual posi: 416[M + H]⁺. MS ESI/APCI Dual nega: 414[M − H]⁻. Na Example 1-295

¹H NMR (300 MHz, METHANOL-d₆) δ ppm 1.40 (s, 6 H) 2.62 (s, 2 H) 3.89 (s, 2 H) 4.61 (s, 2 H) 7.45-7.52 (m, 3 H) 7.86 (s, 1 H) 7.97-8.04 (m, 2 H). MS ESI/APCI Dual posi: 400[M + H]⁺. MS ESI/APCI Dual nega: 398[M − H]⁻. Na Example 1-296

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.54-0.73 (m, 2 H) 0.87- 1.01 (m, 2 H) 1.82-2.00 (m, 1 H) 2.50-2.58 (m, 2 H) 3.22- 3.39 (m, 2 H) 3.47 (d, J = 4.4 Hz, 2 H) 4.51 (s, 2 H) 6.86- 7.03 (m, 3 H) 7.04-7.19 (m, 2 H) 7.74 (dd, J = 8.4, 2.6 Hz, 1 H) 8.06 (d, J = 2.6 Hz, 1 H) 9.90-10.20 (m, 1 H). MS ESI/APCI Dual posi: 438[M + H]⁺. MS ESI/APCI Dual nega: 436[M − H]⁻. Na Example 1-297

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.24 (s, 3 H) 2.54-2.68 (m, 2 H) 3.37 (t, J = 7.1 Hz, 2 H) 3.72 (d, J = 5.0 Hz, 2 H) 4.57 (s, 2 H) 6.92 (d, J = 8.4 Hz, 1 H) 7.01-7.09 (m, 2 H) 7.25-7.34 (m, 2 H) 7.67 (ddd, J = 8.4, 2.5, 0.6 Hz, 1 H) 7.97 (dt, J = 2.5, 0.6 Hz, 1 H) 10.01-10.19 (m, 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺. MS ESI/APCI Dual nega: 410[M − H]⁻. Na

TABLE 21-43 Compound Salt No. Structure Analytical Data information Example 1-298

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.59-2.81 (m, 2 H) 3.44 (t, J = 7.3 Hz, 2 H) 4.03 (d, J = 5.8 Hz, 2 H) 4.61 (s, 2 H) 7.15-7.21 (m, 2 H) 7.24 (d, J = 8.7 Hz, 1 H) 7.37 (d, J = 8.7 Hz, 2 H) 8.12-8.28 (m, 1 H) 8.56 (dd, J = 1.8, 0.9 Hz, 1 H) 10.07 (br. s., 1 H). MS ESI/APCI Dual posi: 466[M + H]⁺. MS ESI/APCI Dual nega: 464[M − H]⁻. HCl Example 1-299

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.31 (s, 6 H) 2.78-2.89 (m, 2 H) 3.85 (s, 3 H) 4.01 (d, J = 4.5 Hz, 2 H) 4.65 (br. s., 2 H) 6.60 (br. s., 1 H) 7.20-7.29 (m, 1 H) 7.31-7.39 (m, 2 H) 7.72-7.80 (m, 2 H) 9.93-10.06 (m, 1 H). MS ESI/APCI Dual posi: 413[M + H]⁺. MS ESI/APCI Dual nega: 411[M − H]⁻. HCl Example 1-300

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.29 (s, 6 H) 2.64-2.76 (m, 2 H) 3.81 (s, 3 H) 3.96-4.06 (m, 2 H) 4.49-4.65 (m, 2 H) 6.28 (br. s., 1 H) 7.36-7.56 (m, 5 H) 10.02-10.20 (m, 1 H). MS ESI/APCI Dual posi: 413[M + H]⁺. MS ESI/APCI Dual nega: 411[M − H]⁻. HCl Example 1-301

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.36 (s, 6 H) 2.22 (s, 3 H) 2.50-2.80 (m, 2 H) 4.04 (d, J = 5.8 Hz, 2 H) 4.70 (br. s., 2 H) 7.44-7.57 (m, 3 H) 7.85-7.94 (m, 2 H) 10.00 (br. s., 1 H). MS ESI/APCI Dual posi: 414[M + H]⁺. MS ESI/APCI Dual nega: 412[M − H]⁻. HCl Example 1-302

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.26-0.35 (m, 2 H) 0.51- 0.60 (m, 2 H) 0.95 (s, 6 H) 1.12-1.30 (m, 1 H) 2.96-3.07 (m, 2 H) 3.40-3.48 (m, 2 H) 3.78 (d, J = 7.0 Hz, 2 H) 4.48 (s, 2 H) 6.87 (d, J = 8.5 Hz, 2 H) 7.21 (d, J = 8.5 Hz, 2 H). MS ESI/APCI Dual posi: 403[M + H]⁺. MS ESI/APCI Dual nega: 401[M − H]⁻. Na Example 1-303

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.64 (s, 2 H) 0.89 (s, 2 H) 2.31 (s, 3 H) 2.45 (s, 2 H) 3.66 (d, J = 4.5 Hz, 2 H) 4.43 (s, 2 H) 6.90-6.96 (m, 1 H) 6.97-7.03 (m, 2 H) 7.15-7.25 (m, 2 H) 7.66-7.77 (m, 1 H) 8.02-8.10 (m, 1 H) 9.93- 10.30 (m, 1 H). MS ESI/APCI Dual posi: 438[M + H]⁺. MS ESI/APCI Dual nega: 436[M − H]⁻. Na Example 1-304

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.01 (s, 6 H) 3.15 (s, 2 H) 3.40-3.49 (m, 2 H) 4.59 (s, 2 H) 7.36-7.45 (m, 1 H) 7.51- 7.58 (m, 1 H) 7.60-7.64 (m, 1 H) 9.95-10.48 (m, 1 H). MS ESI/APCI Dual posi: 451[M + H]⁺. MS ESI/APCI Dual nega: 449[M − H]⁻.

TABLE 21-44 Compound Salt No. Structure Analytical Data information Example 1-305

¹H NMR (300 MHz, METHANOL-d₆) δ ppm 2.33 (s, 3 H) 2.41-2.63 (m, 2 H) 3.27-3.33 (m, 2 H) 3.88 (s, 2 H) 4.54 (s, 2 H) 5.01 (s, 2 H) 6.94 (d, J = 8.7 Hz, 2 H) 7.13-7.25 (m, 4 H) 7.30 (d, J = 8.1 Hz, 2 H). MS ESI/APCI Dual posi: 425[M + H]⁺. MS ESI/APCI Dual nega: 423[M − H]⁻. Example 1-306

¹H NMR (300 MHz, METHANOL-d₆) δ ppm 2.44-2.63 (m, 2 H) 3.29-3.33 (m, 2 H) 3.89 (s, 2 H) 4.55 (s, 2 H) 5.07 (s, 2 H) 6.93-6.99 (m, 2 H) 7.24 (d, J = 8.7 Hz, 2 H) 7.27-7.33 (m, 1 H) 7.33-7.38 (m, 2 H) 7.45 (s, 1 H). MS ESI/APCI Dual posi: 445[M + H]⁺. MS ESI/APCI Dual nega: 443[M − H]⁻. Example 1-307

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.00-1.20 (m, 1 H) 1.25-1.56 (m, 4 H) 1.61-1.92 (m, 5 H) 2.47-2.67 (m, 2 H) 3.25-3.45 (m, 2 H) 4.12-4.22 (m, 2 H) 4.21-4.53 (m, 1 H) 10.20-10.47 (m, 1 H). MS ESI/APCI Dual posi: 297[M + H]⁺, 319[M + Na]⁺. MS ESI/APCI Dual nega: 295[M − H]⁻.

TABLE 21-45 Compound Salt No. Structure Analytical Data information Example 1-308

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.35-2.66 (m, 2 H) 3.18- 3.40 (m, 2 H) 3.99 (d, J = 5.8 Hz, 2 H) 9.91-10.02 (m, 1 H). MS ESI/APCI Dual nega: 213[M − H]⁻. Example 1-309

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.62-2.75 (m, 2 H) 2.84- 2.98 (m, 3 H) 3.34-3.48 (m, 2 H) 3.95-4.03 (m, 2 H) 10.02-10.17 (m, 1 H). MS ESI/APCI Dual posi: 251[M + H]⁺. MS ESI/APCI Dual nega: 227[M − H]⁻. Example 1-310

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.16-1.47 (m, 10 H) 2.31 (s, 2 H) 3.08 (s, 2 H) 3.96 (d, J = 5.7 Hz, 2 H) 4.67 (s, 2 H) 7.22-7.39 (m, 5 H) 8.86 (t, J = 5.7 Hz, 1 H) 12.78 (br. s., 1 H). MS ESI/APCI Dual posi: 387[M + H]⁺, 409[M + H]⁺. MS ESI/APCI Dual nega: 385[M − H]⁻. Example 1-311

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.55-1.68 (m, 2 H) 2.03- 2.18 (m, 2 H) 2.83-2.92 (m, 2 H) 2.94-3.07 (m, 4 H) 3.63- 3.77 (m, 2 H) 4.56-4.81 (m, 2 H) 7.24-7.35 (m, 3 H) 7.41 (t, J = 7.8 Hz, 2 H) 7.54-7.61 (m, 4 H) 10.03-10.19 (m, 1 H). MS ESI/APCI Dual posi: 450[M + H]⁺. MS ESI/APCI Dual nega: 448[M − H]⁻. Example 1-312

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.11-1.53 (m, 10 H) 2.34 (s, 2 H) 3.11 (s, 2 H) 3.97 (d, J = 5.8 Hz, 2 H) 4.71 (s, 2 H) 7.31-7.41 (m, 3 H) 7.42-7.51 (m, 2 H) 7.60-7.70 (m, 4 H) 8.88 (t, J = 5.5 Hz, 1 H). MS ESI/APCI Dual posi: 463[M + H]⁺, 485[M + Na]⁺. MS ESI/APCI Dual nega: 461[M − H]⁻. Example 1-313

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.42-2.46 (m, 2 H) 3.82- 3.93 (m, 2 H) 3.95-4.04 (m, 2 H) 4.22-4.30 (m, 2 H) 4.95- 5.07 (m, 2 H) 7.29-7.39 (m, 3 H) 7.40-7.46 (m, 2 H) 7.57-7.66 (m, 4 H) 9.73-9.85 (m, 1 H). HCL Example 1-314

¹H NMR (300 MHz, METHANOL-d₆) δ ppm 2.30-2.44 (m, 1 H) 2.79-3.04 (m, 3 H) 3.40-3.47 (m, 1 H) 3.55-3.65 (m, 1 H) 4.03 (s, 2 H) 4.69-4.81 (m, 1 H) 4.94-5.06 (m, 1 H) 7.28-7.45 (m, 5 H) 7.55-7.65 (m, 4 H). MS ESI/APCI Dual posi: 472[M + Na]⁺. MS ESI/APCI Dual nega: 448[M − H]⁻.

TABLE 21-46 Compound Salt No. Structure Analytical Data information Example 1-315

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.34-2.46 (m, 1 H) 2.61- 2.75 (m, 4 H) 2.90-3.04 (m, 1 H) 3.04-3.19 (m, 1 H) 3.38- 3.57 (m, 2 H) 3.96-4.09 (m, 2 H) 4.57-4.88 (m, 2 H) 7.31-7.40 (m, 3 H) 7.42-7.50 (m, 2 H) 7.58-7.68 (m, 4 H) 9.89-10.30 (m, 1 H). MS ESI/APCI Dual posi: 486[M + Na]⁺. MS ESI/APCI Dual nega: 462[M − H]⁻. Example 1-316

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.66-2.76 (m, 2 H) 3.38- 3.46 (m, 2 H) 3.94-4.04 (m, 2 H) 4.64 (s, 2 H) 7.46 (d, J = 8.0 Hz, 2 H) 7.80 (d, J = 8.0 Hz, 2 H) 9.14 (s, 2 H) 9.18 (s, 1 H) 9.99-10.08 (m, 1 H). MS ESI/APCI Dual posi: 383[M + H]⁺, 405[M + Na]⁺. MS ESI/APCI Dual nega: 381[M − H]⁻. Example 1-317

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.73-0.98 (m, 3 H) 1.16-1.38 (m, 12 H) 1.44-1.65 (m, 2 H) 2.52-2.72 (m, 2 H) 3.31-3.48 (m, 4 H) 4.11-4.21 (m, 2 H) 10.16-10.39 (m, 1 H). MS ESI/APCI Dual posi: 341[M + H]⁺, 363[M + Na]⁺. MS ESI/APCI Dual nega: 339[M − H]⁻. Example 1-318

¹H NMR (500 MHz, METHANOL-d₆) δ ppm 3.96 (s, 2 H) 4.11 (s, 2 H) 4.64 (s, 2 H) 7.29-7.36 (m, 3 H) 7.39-7.45 (m, 2 H) 7.57-7.63 (m, 4 H). MS ESI/APCI Dual posi: 367[M + H]⁺. MS ESI/APCI Dual nega: 365[M − H]⁻. Example 1-319

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.88-1.00 (m, 6 H) 1.78-2.16 (m, 1 H) 2.49-2.80 (m, 2 H) 3.10-3.33 (m, 2 H) 3.33-3.60 (m, 2 H) 4.07-4.27 (m, 2 H) 10.04-10.44 (m, 1 H). MS ESI/APCI Dual posi: 271[M + H]⁺, 293[M + Na]⁺. MS ESI/APCI Dual nega: 269[M − H]⁻. Example 1-320

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.68-2.78 (m, 2 H) 3.51 (t, J = 7.2 Hz, 2 H) 3.97-4.04 (m, 2 H) 4.59 (s, 2 H) 8.77 (s, 1 H) 9.11 (s, 1 H). MS ESI/APCI Dual posi: 307[M + H]⁺, 329[M + Na]⁺. MS ESI/APCI Dual nega: 305[M − H]⁻. HCL Example 1-321

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.36-1.61 (m, 6 H) 2.63-2.70 (m, 2 H) 3.24-3.27 (m, 2 H) 3.33-3.39 (m, 2 H) 3.45-3.58 (m, m2 H) 3.91-4.03 (m, 2 H) 4.53-4.64 (m, 2 H) 7.24-7.35 (m, 4 H) 9.92-10.02 (m, 1 H). MS ESI/APCI Dual posi: 416[M + H]⁺, 438[M + Na]⁺. MS ESI/APCI Dual nega: 414[M − H]⁻.

TABLE 21-47 Compound Salt No. Structure Analytical Data information Example 1-322

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.84 (t, J = 7.4 Hz, 3 H) 1.44- 1.563 (m, 2 H) 2.61-2.68 (m, 2 H) 3.13-3.20 (m, 2 H) 3.32-3.41 (m, 2 H) 3.93-4.03 (m, 2 H) 4.55-4.64 (m, 2 H) 7.27-7.35 (m, 2 H) 7.74-7.80 (m, 2 H) 8.33-8.41 (m, 1 H) 9.91-10.22 (m, 1 H). MS ESI/APCI Dual posi: 390[M + H]⁺. MS ESI/APCI Dual nega: 388[M − H]⁻. 412[M + Na]⁺. Example 1-323

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.40 (d, J = 7.0 Hz, 3 H) 3.96-4.04 (m, 1 H) 4.14 (d, J = 15.7 Hz, 1 H) 4.21 (m, 2 H) 5.13 (d, J = 15.7 Hz, 1 H) 7.30 (m, 2 H) 7.32-7.38 (m, 1 H) 7.40-7.47 (m, 2 H) 7.51-7.61 (m, 4 H) 8.22 (t, J = 5.8 Hz, 1 H). MS ESI/APCI Dual posi: 381[M + H]⁺. MS ESI/APCI Dual nega: 379[M − H]⁻. Example 1-324

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 6 H) 4.21 (d, J = 6.2 Hz, 2 H) 4.60 (s, 2 H) 7.32-7.39 (m, 3 H) 7.43 (m, 2 H) 7.53-7.60 (m, 4 H) 8.27 (m, 1 H). MS ESI/APCI Dual posi: 395[M + H]⁺. MS ESI/APCI Dual nega: 393[M − H]⁻. Example 1-325

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.06-1.19 (m, 1 H) 1.56-1.81 (m, 7 H) 1.87-2.00 (m, 2 H) 4.16-4.25 (m, 2 H) 4.59 (s, 2 H) 7.29-7.37 (m, 3 H) 7.38-7.47 (m, 2 H) 7.50-7.61 (m, 4 H) 8.28-8.31 (m, 1 H). MS ESI/APCI Dual posi: 435[M + H]⁺. MS ESI/APCI Dual nega: 433[M − H]⁻. Example 1-326

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 3.68 (d, J = 15.3 Hz, 1 H) 4.21-4.27 (m, 2 H) 4.87 (s, 1 H) 5.23 (d, J = 15.3 Hz, 1 H) 7.14-7.22 (m, 4 H) 7.32-7.39 (m, 1 H) 7.39-7.48 (m, 5 H) 7.50-7.61 (m, 4 H) 8.23-8.32 (m, 1 H). MS ESI/APCI Dual posi: 443[M + H]⁺. MS ESI/APCI Dual nega: 441[M − H]⁻. Example 1-327

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.64-2.72 (m, 2 H) 3.16 (s, 3 H) 3.37-3.45 (m, 2 H) 3.93-4.04 (m, 2 H) 4.59- 4.72 (m, 2 H) 7.47-7.56 (m, 2 H) 7.78-7.92 (m, 2 H) 9.80- 10.29 (m, 1 H). MS ESI/APCI Dual posi: 383[M + H]⁺, 405[M + Na]⁺. MS ESI/APCI Dual nega: 381[M − H]⁻. Example 1-328

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.03-1.79 (m, 10 H) 2.67- 3.00 (m, 2 H) 3.14-3.23 (m, 3 H) 3.93-4.10 (m, 2 H) 4.77- 4.92 (m, 2 H) 7.48-7.62 (m, 2 H) 7.80-7.94 (m, 2 H) 9.87-10.26 (m, 1 H) 12.84 (br. s., 1 H). MS ESI/APCI Dual posi: 473[M + Na]⁺. MS ESI/APCI Dual nega: 449[M − H]⁻.

TABLE 21-48 Compound Salt No. Structure Analytical Data information Example 1-329

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.01-1.24 (m, 1 H) 1.54-2.07 (m, 9 H) 4.20 (d, J = 5.9 Hz, 2 H) 4.60 (s, 2 H) 7.29-7.41 (m, 2 H) 7.48-7.59 (m, 2 H) 7.59-7.73 (m, 4 H) 8.16-8.33 (m, 1 H). MS ESI/APCI Dual posi: 503[M + H]⁺, 525[M + Na]⁺. MS ESI/APCI Dual nega: 501[M − H]⁻. Example 1-330

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.02-1.24 (m, 1 H) 1.29-2.10 (m, 18 H) 4.19 (d, J = 5.8 Hz, 2 H) 4.58 (s, 2 H) 7.20-7.36 (m, 2 H) 7.36-7.58 (m, 6 H) 8.20-8.34 (m, 1 H). MS ESI/APCI Dual posi: 491[M + H]⁺, 513[M + Na]⁺. MS ESI/APCI Dual nega: 489M − H]⁻. Example 1-331

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.93-1.14 (m, 2 H) 1.15-1.63 (m, 6 H) 1.71-1.89 (m, 2 H) 3.02-3.08 (m, 3 H) 3.24 (s, 2 H) 4.14-4.23 (m, 2 H) 4.66-4.75 (m, 2 H) 7.45-7.56 (m, 2 H) 7.85-8.01 (m, 2 H) 10.14-10.69 (m, 1 H). MS ESI/APCI Dual posi: 451[M + H]⁺, 473[M + Na]⁺. MS ESI/APCI Dual nega: 449[M − H]⁻. Example 1-332

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.95-2.16 (m, 19 H) 2.37-2.58 (m, 1 H) 3.00-3.19 (m, 2 H) 4.08-4.26 (m, 2 H) 7.10-7.37 (m, 5 H) 8.18-8.34 (m, 1 H). MS ESI/APCI Dual posi: 441[M + H]⁺, 463[M + Na]⁺. MS ESI/APCI Dual nega: 439[M − H]⁻. Example 1-333

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 2.47 (s, 3 H) 2.51-2.54 (m, 2 H) 3.30-3.35 (m, 2 H) 3.43 (d, J = 4.4 Hz, 2 H) 4.49 (s, 2 H) 7.26-7.32 (m, 1 H) 7.48 (dd, J = 8.4, 2.8 Hz, 1 H) 7.61-7.65 (m, 1 H) 7.83-7.88 (m, 1 H) 8.27 (dd, J = 2.8, 0.5 Hz, 1 H) 9.89-10.03 (m, 1 H). MS ESI/APCI Dual posi: 427[M + H]⁺. MS ESI/APCI Dual nega: 425[M − H]⁻. Na Example 1-334

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.49-3.74 (m, 2 H) 3.87 (d, J = 5.3 Hz, 2 H) 4.66 (s, 2 H) 7.33-7.54 (m, 2 H) 7.60- 7.74 (m, 2 H) 9.99-10.20 (m, 1 H). MS ESI/APCI Dual posi: 409[M + H]⁺. MS ESI/APCI Dual nega: 407[M − H]⁻. Na Example 1-335

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.64-2.79 (m, 2 H) 3.35- 3.49 (m, 2 H) 3.94-4.13 (m, 2 H) 4.57-4.76 (m, 2 H) 7.29- 7.49 (m, 2 H) 7.83-8.01 (m, 2 H) 9.93-10.30 (m, 1 H).

TABLE 21-49 Compound Salt No. Structure Analytical Data information Example 1-336

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.73-2.86 (m, 2 H) 3.63 (t, J = 7.1 Hz, 2 H) 4.01 (d, J = 5.7 Hz, 2 H) 4.83 (s, 2 H) 7.68 (d, J = 8.2 Hz, 1 H) 8.11 (dd, J = 8.2, 5.7 Hz, 1 H) 8.45 (d, J = 7.8 Hz, 1 H) 8.83-8.97 (m, 2 H) 9.12 (d, J = 2.0 Hz, 1 H) 9.35 (d, J = 2.0 Hz, 1 H) 9.90 (br. s., 1 H). MS ESI/APCI Dual posi: 383[M + H]⁺. HCl Example 1-337

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.62 (br. s., 2 H) 3.37 (t, J = 7.1 Hz, 2 H) 3.80 (s, 3 H) 4.02 (d, J = 5.8 Hz, 2 H) 4.38 (s, 2 H) 7.39 (s, 1 H) 7.66 (s, 1 H) 10.09 (br. s., 1 H). MS ESI/APCI Dual posi: 309[M + H]⁺. HCl Example 1-338

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.76 (t, J = 6.6 Hz, 2 H) 3.52- 3.62 (m, 2 H) 4.01 (br. s., 2 H) 4.69 (s, 2 H) 9.02 (s, 2 H) 9.86 (br. s., 1 H). MS ESI/APCI Dual nega: 373[M − H]⁻. HCl Example 1-339

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.53 (s, 3 H) 2.73 (t, J = 7.1 Hz, 2 H) 3.31-3.52 (m, 4 H) 4.00-4.09 (m, 2 H) 4.49- 4.66 (m, 2 H) 7.39-7.54 (m, 1 H) 9.82-10.29 (m, 1 H). MS ESI/APCI Dual posi: 309[M + H]⁺. HCl Example 1-340

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.63-2.75 (m, 2 H) 3.33- 3.49 (m, 6 H) 3.66-3.76 (m, 4 H) 4.02 (d, J = 5.6 Hz, 2 H) 4.55 (s, 2 H) 7.30 (s, 1 H) 9.91 (br. s., 1 H). MS ESI/APCI Dual posi: 397[M + H]⁺. MS ESI/APCI Dual nega: 395[M − H]⁻. HCl Example 1-341

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.34 (d, J = 0.9 Hz, 3 H) 2.61-2.79 (m, 2 H) 3.42-3.62 (m, 2 H) 4.02 (d, J = 5.8 Hz, 2 H) 4.81 (s, 2 H) 7.22 (s, 1 H) 8.06-8.39 (m, 1 H) 9.75- 10.04 (m, 1 H). MS ESI/APCI Dual posi: 326[M + H]⁺. HCl Example 1-342

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.64 (br. s., 2 H) 2.98- 3.20 (m, 4 H) 3.27-3.38 (m, 2 H) 3.43-3.52 (m, 2 H) 3.57 (s, 3 H) 3.79 (d, J =11.3 Hz, 2 H) 4.02 (d, J = 5.6 Hz, 2 H) 4.49 (br. s., 2 H) 6.97 (d, J = 8.7 Hz, 2 H) 7.19 (d, JU = 8.7 Hz, 2 H) 9.94-10.84 (m, 1 H). MS ESI/APCI Dual posi: 403[M + H]⁺. MS ESI/APCI Dual nega: 401[M − H]⁻. HCl

TABLE 21-50 Compound Salt No. Structure Analytical Data information Example 1-343

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.95-2.08 (m, 2 H) 2.62 (s, 6 H) 2.97 (br. s., 2 H) 3.29-3.39 (m, 4 H) 3.93-4.05 (m, 4 H) 4.50 (s, 2 H) 8.90 (d, J = 8.4 Hz, 2 H) 7.22 (d, J = 8.4 Hz, 2 H) 10.08 (br. s., 1 H). MS ESI/APCI Dual posi: 406[M + H]⁺. MS ESI/APCI Dual nega: 404[M − H]⁻. Na Example 1-344

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.20-3.33 (m, 4 H) 3.51 (d, J = 4.5 Hz, 2 H) 3.69 (t, J = 5.1 Hz, 2 H) 3.91-4.00 (m, 2 H) 4.48 (s, 2 H) 6.85-6.94 (m, 2 H) 7.15-7.24 (m, 2 H) 10.09 (br. s., 1 H). MS ESI/APCI Dual posi: 365[M + H]⁺. Na Example 1-345

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.69 (t, J = 7.1 Hz, 2 H) 2.82 (d, J = 4.8 Hz, 6 H) 3.18-3.32 (m, 2 H) 3.39 (t, J = 7.1 Hz, 2 H) 3.56-3.68 (m, 2 H) 4.02 (d, J = 5.6 Hz, 2 H) 4.57-4.71 (m, 2 H) 7.38 (d, J = 8.2 Hz, 2 H) 7.89 (d, J = 8.2 Hz, 2 H) 8.72-8.87 (m, 1 H) 9.90-10.28 (m, 1 H). MS ESI/APCI Dual posi: 419[M + H]⁺. MS ESI/APCI Dual nega: 417[M − H]⁻. HCl Example 1-346

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.65 (t, J = 7.1 Hz, 2 H) 3.29- 3.39 (m, 2 H) 4.02 (d, J = 5.8 Hz, 2 H) 4.43-4.57 (m, 2 H) 4.64 (s, 2 H) 6.87 (d, J = 8.7 Hz, 2 H) 7.21 (d, J = 8.7 Hz, 2 H) 10.01-10.27 (m, 1 H). MS ESI/APCI Dual posi: 379[M + H]⁺. MS ESI/APCI Dual nega: 377[M − H]⁻. Example 1-347

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.52-2.60 (m, 2 H) 3.25- 3.39 (m, 4 H) 3.45-3.54 (m, 2 H) 3.58 (d, J = 4.5 Hz, 2 H) 4.60 (s, 2 H) 7.34 (d, J = 8.4 Hz, 2 H) 7.82 (d, J = 8.4 Hz, 2 H) 8.47 (t, J = 5.7 Hz, 1 H) 10.12 (br. s., 1 H). MS ESI/APCI Dual posi: 392[M + H]⁺. MS ESI/APCI Dual nega: 390[M − H]⁻. Na Example 1-348

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.70 (t, J = 7.0 Hz, 2 H) 3.40 (t, J = 7.0 Hz, 2 H) 4.02 (d, J = 5.6 Hz, 2 H) 4.64 (s, 2 H) 4.78 (d, J = 5.6 Hz, 2 H) 7.41 (d, J = 8.2 Hz, 2 H) 7.73-7.87 (m, 2 H) 7.93 (d, J = 8.2 Hz, 2 H) 8.36 (td, J = 7.8, 1.6 Hz, 1 H) 8.77 (dd, J = 5.5, 0.9 Hz, 1 H) 9.33-9.48 (m, 1 H) 9.95- 10.29 (m, 1 H). MS ESI/APCI Dual posi: 439[M + H]⁺. MS ESI/APCI Dual nega: 437[M − H]⁻. HCl Example 1-349

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.69 (t, J = 7.0 Hz, 2 H) 3.29 (t, J = 6.4 Hz, 2 H) 3.38 (t, J = 7.0 Hz, 2 H) 3.72 (q, J = 6.3 Hz, 2 H) 4.02 (d, J = 5.4 Hz, 2 H) 4.53-4.71 (m, 2 H) 7.34 (d, J = 8.2 Hz, 2 H) 7.75 (d, J = 8.2 Hz, 2 H) 7.81-7.93 (m, 2 H) 8.41 (td, J = 7.8, 1.6 Hz, 1 H) 8.68 (t, J = 5.8 Hz, 1 H) 8.79 (d, J = 5.8 Hz, 1 H) 9.92-10.27 (m, 1 H). MS ESI/APCI Dual posi: 453[M + H]⁺. MS ESI/APCI Dual nega: 451[M − H]⁻. HCl

TABLE 21-51 Compound Salt No. Structure Analytical Data information Example 1-350

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.83-1.97 (m, 2 H) 2.11- 2.22 (m, 2 H) 2.61-2.77 (m, 2 H) 3.28-3.46 (m, 8 H) 4.02 (d, J = 5.6 Hz, 2 H) 4.62 (s, 2 H) 7.36 (d, J = 8.2 Hz, 2 H) 7.77 (d, J = 8.2 Hz, 2 H) 8.44-8.58 (m, 1 H) 10.02 (br. s., 1 H). MS ESI/APCI Dual posi: 459[M + H]⁺. MS ESI/APCI Dual nega: 457[M − H]⁻. HCl Example 1-351

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.63-2.79 (m, 2 H) 3.31- 3.47 (m, 2 H) 3.91 (d, J = 5.9 Hz, 2 H) 3.97-4.10 (m, 2 H) 4.56-4.73 (m, 2 H) 7.38 (d, J = 8.2 Hz, 2 H) 7.84 (d, J = 8.2 Hz, 2 H) 8.80 (t, J = 5.8 Hz, 1 H) 9.92-10.29 (m, 1 H). MS ESI/APCI Dual posi: 406[M + H]⁺. MS ESI/APCI Dual nega: 404[M − H]⁻. Example 1-352

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.79-1.02 (m, 2 H) 1.14- 1.35 (m, 1 H) 1.80-1.97 (m, 1 H) 3.04-3.71 (m, 8 H) 6.85- 7.26 (m, 4 H) 9.84-10.29 (m, 1 H). MS ESI/APCI Dual posi: 363[M + H]⁺. MS ESI/APCI Dual nega: 361[M − H]⁻. Na Example 1-353

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.52-2.61 (m, 2 H) 3.38- 3.53 (m, 4 H) 4.84 (s, 2 H) 7.03-7.14 (m, 2 H) 7.29-7.37 (m, 1 H) 7.40-7.50 (m, 3 H) 8.34 (d, J = 2.8 Hz, 1 H) 9.92- 10.23 (m, 1 H). MS ESI/APCI Dual posi: 432[M + H]⁺. MS ESI/APCI Dual nega: 430[M − H]⁻. Na Example 1-354

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.66 (br. s., 2 H) 3.42 (t, J = 7.1 Hz, 2 H) 3.74 (s, 3 H) 4.02 (d, J = 5.6 Hz, 2 H) 4.55 (s, 2 H) 6.64-6.74 (m, 2 H) 6.75-6.83 (m, 1 H) 6.99 (d, J = 8.4 Hz, 1 H) 7.30 (t, J = 8.4 Hz, 1 H) 7.78 (dd, J = 8.4, 2.5 Hz, 1 H) 8.13 (d, J = 2.5 Hz, 1 H) 10.02 (br. s., 1 H). MS ESI/APCI Dual posi: 428[M + H]⁺. MS ESI/APCI Dual nega: 426[M − H]⁻. HCl Example 1-355

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.43-2.49 (m, 2 H) 3.24- 3.32 (m, 2 H) 3.48 (d, J = 4.5 Hz, 2 H) 4.55 (s, 2 H) 7.03- 7.11 (m, 2 H) 7.32-7.35 (m, 2 H) 7.51 (d, J = 1.9 Hz, 2 H) 8.20-8.22 (m, 1 H) 10.08 (br. s., 1 H). MS ESI/APCI Dual posi: 432[M + H]⁺. MS ESI/APCI Dual nega: 430[M − H]⁻. Na Example 1-356

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.51-2.59 (m, 2 H) 3.39- 3.52 (m, 4 H) 4.67 (s, 2 H) 7.19 (d, J = 8.5 Hz, 2 H) 7.38 (d, J = 8.5 Hz, 1 H) 7.58 (dd, J = 8.5, 2.8 Hz, 1 H) 7.70-7.81 (m, 2 H) 8.41 (d, J = 2.8 Hz, 1 H) 9.94-10.12 (m, 1 H). MS ESI/APCI Dual posi: 466[M + H]⁺. MS ESI/APCI Dual nega: 464[M − H]⁻. Na

TABLE 21-52 Compound Salt No. Structure Analytical Data information Example 1-357

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.54-2.03 (m, 4 H) 2.18- 2.37 (m, 2 H) 3.37-3.48 (m, 4 H) 4.61 (s, 2 H) 7.35-7.44 (m, 1 H) 7.51-7.62 (m, 2 H). MS ESI/APCI Dual posi: 463[M + H]⁺. MS ESI/APCI Dual nega: 461[M − H]⁻. Na Example 1-358

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00 (s, 6 H) 3.01-3.17 (m, 2 H) 3.39-3.49 (m, 2 H) 3.89 (s, 3 H) 4.61 (s, 2 H) 6.85-6.95 (m, 1 H) 7.34-7.45 (m, 2 H) 7.59-7.69 (m, 2 H) 7.95-8.05 (m, 1 H) 8.43-8.51 (m, 1 H). MS ESI/APCI Dual posi: 440[M + H]⁺. MS ESI/APCI Dual nega: 438[M − H]⁻. Na Example 1-359

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.57-0.82 (m, 4 H) 0.97 (s, 6 H) 3.05 (s, 2 H) 3.45 (d, J = 4.4 Hz, 2 H) 3.75-3.85 (m, 1 H) 4.50 (s, 2 H) 6.95-7.06 (m, 2 H) 7.18-7.29 (m, 2 H). MS ESI/APCI Dual posi: 389[M + H]⁺. MS ESI/APCI Dual nega: 387[M − H]⁻. Na Example 1-360

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.31-0.36 (m, 2 H) 0.54- 0.80 (m, 2 H) 1.19-1.27 (m, 1 H) 3.22-3.38 (m, 4 H) 3.45- 3.52 (m, 2 H) 3.89 (d, J = 7.0 Hz, ,2 H) 4.47 (s, 2 H) 7.05- 7.10 (m, 1 H) 7.17-7.21 (m, 1 H) 7.31-7.35 (m, 1 H). MS ESI posi: 409[M + H]⁺. MS ESI nega: 407[M − H]⁻. Na Example 1-361

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.59-2.01 (m, 4 H) 2.19- 2.38 (m, 2 H) 3.42-3.48 (m, 2 H) 3.70-3.79 (m, 2 H) 3.89 (s, 3 H) 4.64 (s, 2 H) 6.90 (d, J = 8.5 Hz, 1 H) 7.39 (d, J = 8.2 Hz, 2 H) 7.65 (d, J = 8.2 Hz, 2 H) 7.95-8.07 (m, 1 H) 8.42-8.53 (m, 1 H). MS ESI/APCI Dual posi: 452[M + H]⁺. Na Example 1-362

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.57-0.69 (m, 2 H) 0.82- 1.06 (m, 8 H) 1.81-1.95 (m, 1 H) 2.91-3.09 (m, 2 H) 3.38- 3.46 (m, 2 H) 4.51 (s, 2 H) 6.98-7.07 (m, 2 H) 7.12- 7.20 (m, 2 H). MS ESI/APCI Dual posi: 373[M + H]⁺. MS ESI/APCI Dual nega: 371[M − H]⁻. Na Example 1-363

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.56-0.83 (m, 4 H) 1.47- 1.96 (m, 4 H) 2.13-2.34 (m, 2 H) 3.40-3.49 (m, 2 H) 3.75- 3.87 (m, 1 H) 4.51 (s, 2 H) 6.96-7.07 (m, 2 H) 7.18- 7.29 (m, 2 H). Na

TABLE 21-53 Compound Salt No. Structure Analytical Data information Example 1-364

¹H NMR (300 MHz, METHANOL-d₆) δ ppm 2.34 (s, 3 H) 2.46- 2.59 (m, 2 H) 3.27-3.34 (m, 2 H) 3.89 (s, 2 H) 4.55 (s, 2 H) 5.02 (s, 2 H) 6.90-6.99 (m, 2 H) 7.07-7.15 (m, 1 H) 7.17-7.27 (m, 5 H). MS ESI/APCI Dual posi: 425[M + H]⁺. MS ESI/APCI Dual nega: 423[M − H]⁻. Na Example 1-365

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.51-2.56 (m, 2 H) 3.26- 3.35 (m, 2 H) 3.49 (d, J = 4.5 Hz, 2 H) 4.59 (s, 2 H) 7.13- 7.22 (m, 2 H) 7.33-7.44 (m, 2 H) 7.48-7.57 (m, 1 H) 7.88 (d, J = 8.5 Hz, 1 H) 8.55 (d, J = 3.0 Hz, 1 H) 10.09 (br. s., 1 H). MS ESI/APCI Dual posi: 466[M + H]⁺. MS ESI/APCI Dual nega: 464[M − H]⁻. Na Example 1-366

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.32 (s, 3 H) 2.42-2.48 (m, 2 H) 3.27-3.37 (m, 2 H) 3.48 (d, J = 4.5 Hz, 2 H) 4.52 (s, 2 H) 6.98-7.07 (m, 2 H) 7.24 (d, J = 2.5 Hz, 1 H) 7.37 (d, J = 8.5 Hz, 1 H) 7.77 (dd, J = 8.5, 2.5 Hz, 1 H) 8.09 (d, J = 2.0 Hz, 1 H) 10.06 (d, J = 1.2 Hz, 1 H). MS ESI/APCI Dual posi: 446[M + H]⁺. MS ESI/APCI Dual nega: 444[M − H]⁻. Na Example 1-367

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.23 (d, J = 1.9 Hz, 3 H) 2.52- 2.57 (m, 2 H) 3.26-3.37 (m, 2 H) 3.47-3.53 (m, 2 H) 4.52 (s, 2 H) 6.88 (dd, J = 8.2, 2.5 Hz, 1 H) 6.96-7.05 (m, 3 H) 7.29 (t, J = 8.7 Hz, 1 H) 7.77 (dd, J = 8.7, 2.5 Hz, 1 H) 8.09 (d, J = 1.9 Hz, 1 H) 10.06 (br. s., 1 H). MS ESI/APCI Dual posi: 430[M + H]⁺. MS ESI/APCI Dual nega: 428[M − H]⁻. Na Example 1-368

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.23 (d, J = 1.9 Hz, 3 H) 2.53- 2.59 (m, 2 H) 3.28-3.48 (m, 4 H) 4.51 (s, 2 H) 6.94- 7.02 (m, 2 H) 7.04-7.10 (m, 1 H) 7.16 (t, J = 9.2 Hz, 1 H) 7.76 (dd, J = 8.5, 2.5 Hz, 1 H) 8.07 (d, J = 2.0 Hz, 1 H) 10.04 (br. s., 1 H). MS ESI/APCI Dual posi: 430[M + H]⁺. MS ESI/APCI Dual nega: 428[M − H]⁻. Na Example 1-369

¹H NMR (300 MHz, METHANOL-d₆) δ ppm 2.49-2.61 (m, 2 H) 3.33-3.38 (m, 2 H) 3.89 (s, 2 H) 4.56 (s, 2 H) 5.16 (s, 2 J) 6.93-7.01 (m, 2 H) 7.21-7.29 (m, 2 H) 7.29-7.36 (m, 2 H) 7.39-7.48 (m, 1 H) 7.51-7.59 (m, 1 H). MS ESI/APCI Dual posi: 445[M + H]⁺. MS ESI/APCI Dual nega: 443[M − H]⁻. Na Example 1-370

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.34-0.39 (m, 2 H) 0.47- 0.52 (m, 21 H) 1.16 (s, 3 H) 2.43-2.54 (m, 2 H) 2.99-3.18 (m, 2 H) 3.42 (d, J = 4.1 Hz, 2 H) 3.71 (s, 2 H) 4.45 (s, 2 H) 6.84 (d, J = 8.3 Hz, 2 H) 7.16 (d, J = 8.3 Hz, 2 H). MS ESI/APCI Dual posi: 389[M + H]⁺, 411[M + Na]⁺. MS ESI/APCI Dual nega: 387[M − H]⁻. Na

TABLE 21-54 Compound Salt No. Structure Analytical Data information Example 1-371

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.03-2.21 (m, 4 H) 2.46- 2.64 (m, 3 H) 3.28-3.39 (m, 2 H) 3.40-3.50 (m, 2 H) 3.50- 3.71 (m, 3 H) 7.04-7.16 (m, 2 H) 7.24-7.36 (m, 2 H) 9.74-10.47 (m, 1 H). MS ESI/APCI Dual posi: 377└M + H┘⁺, 399└M + Na┘⁺. MS ESI/APCI Dual nega: 375└M − H┘⁻. Na Example 1-372

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.43-2.46 (m, 2 H) 3.33- 3.35 (m, 2 H) 3.38-3.44 (m, 2 H) 4.46-4.50 (m, 2 H) 5.13 (s, 2 H) 6.97-7.03 (m, 2 H) 7.20-7.25 (m, 2 H) 7.39- 7.45 (m, 1 H) 7.84-7.90 (m, 1 H) 8.52-8.56 (m, 1 H) 8.65- 8.68 (m, 1 H). MS ESI/APCI Dual posi: 412└M + H┘⁺. MS ESI/APCI Dual nega: 410└M − H┘⁻. Na Example 1-373

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 2.46-2.61 (m, 5 H) 3.32-3.34 (m, 2 H) 3.89 (s, 2 H) 4.55 (s, 2 H) 5.12 (s, 2 H) 6.93-7.01 (m, 2 H) 7.18-7.28 (m, 3 H) 7.34-7.40 (m, 1 H) 7.69-7.77 (m, 1 H). MS ESI/APCI Dual posi: 426└M + H┘⁺. MS ESI/APCI Dual nega: 424└M − H┘⁻. Na Example 1-374

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.40-2.49 (m, 2 H) 3.22- 3.29 (m, 2 H) 3.45 (d, J = 4.5 Hz, 2 H) 4.47 (s, 2 H) 5.15 (s, 2 H) 6.98-7.08 (m, 1 H) 7.09-7.17 (m, 1 H) 7.17-7.25 (m, 1 H) 7.29-7.50 (m, 5 H). MS ESI/APCI Dual posi: 429└M + H┘⁺. MS ESI/APCI Dual nega: 427└M − H┘⁻. Na Example 1-375

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.41-2.49 (m, 2 H) 3.19- 3.28 (m, 2 H) 3.45 (d, J = 4.4 Hz, 2 H) 4.48 (s, 2 H) 5.12 (s, 2 H) 6.94-7.02 (m, 2 H) 7.16-7.26 (m, 2 H) 7.34-7.43 (m, 2 H) 7.54-7.62 (m, 2 H). MS ESI/APCI Dual posi: 495└M + H┘⁺. MS ESI/APCI Dual nega: 493└M − H┘⁻. Na Example 1-376

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.19 (t, J = 7.6 Hz, 3 H) 2.40- 2.50 (m, 2 H) 2.54-2.67 (m, 2 H) 3.23-3.35 (m, 2 H) 3.47 (d, J = 4.5 Hz, 2 H) 4.51 (s, 2 H) 6.90-7.07 (m, 3 H) 7.17-7.29 (m, 2 H) 7.75 (dd, J = 8.4, 2.5 Hz, 1 H) 8.07 (s, 1 H). Na Example 1-377

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.91 (t, J = 7.3 Hz, 3 H) 1.50- 1.69 (m, 2 H) 2.49-2.62 (m, 4 H) 3.21-3.42 (m, 2 H) 3.49 (d, J = 4.4 Hz, 2 H) 4.51 (s, 2 H) 6.89-7.07 (m, 3 H) 7.21 (m, J = 8.5 Hz, 2 H) 7.69-7.79 (m, 1 H) 8.03-8.12 (m, 1 H). Na

TABLE 21-55 Compound Salt No. Structure Analytical Data information Example 1-378

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.21 (d, J = 7.0 Hz, 6 H) 2.40-2.50 (m, 2 H) 2.82-2.98 (m, 1 H) 3.19-3.41 (m, 2 H) 3.48 (d, J = 4.4 Hz, 2 H) 4.51 (s, 2 H) 6.85-7.16 (m, 3 H) 7.18-7.36 (m, 2 H) 7.63-7.85 (m, 1 H) 7.97-8.19 (m, 1 H). Na Example 1-379

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.16 (s, 3 H) 2.41-2.55 (m, 2 H) 3.27 (t, J = 7.1 Hz, 2 H) 3.52 (d, J = 4.5 Hz, 2 H) 4.47 (s, 2 H) 4.72 (q, J = 9.0 Hz, 2 H) 6.96-7.04 (m, 1 H) 7.06-7.13 (m, 2 H) 10.10 (br. s., 1 H). MS ESI/APCI Dual posi: 417└M + H┘⁺. MS ESI/APCI Dual nega: 415└M − H┘⁻. Na Example 1-380

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.40-2.50 (m, 2 H) 3.24- 3.31 (m, 2 H) 3.43 (d, J = 4.4 Hz, 2 H) 4.49 (s, 2 H) 5.33 (s, 2 H) 6.82-6.89 (m, 1 H) 7.22-7.50 (m, 5 H) 7.62-7.69 (m, 1 H) 8.09-8.15 (m, 1 H). MS ESI/APCI Dual posi: 412└M + H┘⁺. MS ESI/APCI Dual nega: 410└M − H┘⁻. Na Example 1-381

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.18 (s, 3 H) 2.36-2.47 (m, 2 H) 3.15-3.25 (m, 2 H) 3.46 (d, J = 4.5 Hz, 2 H) 4.45 (s, 2 H) 5.09 (s, 2 H) 6.91-7.01 (m, 1 H) 7.01-7.11 (m, 2 H) 7.21-7.53 (m, 5 H) 9.94-10.22 (m, 1 H). MS ESI/APCI Dual posi: 425└M + H┘⁺. MS ESI/APCI Dual nega: 423└M − H┘⁻. Na Example 1-382

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.33-2.50 (m, 2 H) 2.66- 2.86 (m, 2 H) 3.15-3.31 (m, 2 H) 3.39-3.48 (m, 2 H) 4.18 (t, J = 5.9 Hz, 2 H) 4.48 (s, 2 H) 6.85-6.96 (m, 2 H) 7.22 (m, 2 H) 10.06 (br. s., 1 H). MS ESI/APCI Dual posi: 417└M + H┘⁺. MS ESI/APCI Dual nega: 415└M − H┘⁻. Na Example 1-383

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.12 (s, 3 H) 2.43-2.55 (m, 2 H) 2.78 (qt, J = 11.3, 5.7 Hz, 2 H) 3.19-3.30 (m, 2 H) 3.49 (d, J = 4.5 Hz, 2 H) 4.18 (t, J = 5.7 Hz, 2 H) 4.46 (s, 2 H) 6.86-6.96 (m, 1 H) 7.03-7.11 (m, 2 H) 10.08 (br. s., 1 H). MS ESI/APCI Dual posi: 431└M + H┘+. MS ESI/APCI Dual nega: 429└M − H┘⁻. Na Example 1-384

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.45-2.54 (m, 2 H) 2.71- 2.91 (m, 2 H) 3.23-3.32 (m, 2 H) 3.48 (d, J = 4.5 Hz, 2 H) 4.21-4.29 (m, 2 H) 4.48 (s, 2 H) 7.01-7.24 (m, 3 H) 10.06 (br. s., 1 H). MS ESI/APCI Dual posi: 435└M + H┘+. MS ESI/APCI Dual nega: 433└M − H┘⁻. Na

TABLE 21-56 Compound Salt No. Structure Analytical Data information Example 1-385

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.32 (s, 3 H) 2.40-2.50 (m, 2 H) 3.18-3.42 (m, 2 H) 3.42-3.53 (m, 2 H) 4.64 (s, 2 H) 7.02-7.13 (m, 2 H) 7.18-7.27 (m, 2 H) 8.08-8.16 (m, 1 H) 8.39-8.47 (m, 1 H). MS ESI/APCI Dual posi: 413[M + H]⁺. MS ESI/APCI Dual nega: 411[M − H]⁻. Na Example 1-386

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.19 (s, 6 H) 2.40-2.50 (m, 2 H) 3.23-3.36 (m, 2 H) 3.44 (d, J = 4.4 Hz, 2 H) 4.52 (s, 2 H) 6.68-6.77 (m, 1 H) 6.80-6.86 (m, 1 H) 6.86- 6.96 (m, 2 H) 7.07-7.18 (m, 1 H) 7.21-7.32 (m, 2 H). MS ESI/APCI Dual posi: 425[M + H]⁺. MS ESI/APCI Dual nega: 423[M − H]⁻. Na Example 1-387

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.30 (s, 3 H) 2.49-2.54 (m, 2 H) 3.24-3.30 (m, 2 H) 3.46 (d, J = 4.5 Hz, 2 H) 4.47 (s, 2 H) 6.10 (s, 2 H) 6.99-7.07 (m, 1 H) 7.08-7.24 (m, 4 H) 7.28-7.39 (m, 2 H) 9.89-10.17 (m, 1 H). MS ESI/APCI Dual posi: 443[M + H]⁺. MS ESI/APCI Dual nega: 441[M − H]⁻. Na Example 1-388

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.17 (s, 3 H) 2.43-2.49 (m, 2 H) 3.21-3.28 (m, 2 H) 3.46 (d, J = 4.4 Hz, 2 H) 4.45 (s, 2 H) 5.08 (s, 2 H) 6.91-7.01 (m, 1 H) 7.02-7.11 (m, 2 H) 7.16-7.28 (m, 2 H) 7.45-7.55 (m, 2 H) 9.93-10.17 (m, 1 H). MS ESI/APCI Dual posi: 443[M + H]⁺. MS ESI/APCI Dual nega: 441[M − H]⁻. Na Example 1-389

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.19 (s, 3 H) 2.44-2.49 (m, 2 H) 3.22-3.29 (m, 2 H) 3.46 (d, J = 4.5 Hz, 2 H) 4.46 (s, 2 H) 5.13 (s, 2 H) 6.91-7.01 (m, 1 H) 7.02-7.12 (m, 2 H) 7.34-7.47 (m, 2 H) 7.54-7.55 (m, 2 H) 9.92-10.17 (m, 1 H). MS ESI/APCI Dual posi: 509[M + H]⁺. MS ESI/APCI Dual nega: 507[M − H]⁻. Na Example 1-390

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.03-1.41 (m, 4 H) 1.58- 1.79 (m, 3 H) 2.00-2.13 (m, 2 H) 2.46-2.55 (m, 2 H) 3.19- 3.51 (m, 6 H) 4.17-4.33 (m, 1 H) 6.83-6.98 (m, 3 H) 7.19-7.32 (m, 2 H) 9.91-10.14 (m, 1 H). MS ESI/APCI Dual posi: 403[M + H]⁺. MS ESI/APCI Dual nega: 401[M − H]⁻. Na Example 1-391

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.21-1.64 (m, 6 H) 1.66- 1.96 (m, 3 H) 2.47-2.56 (m, 2 H) 3.19-3.45 (m, 6 H) 4.52- 4.60 (m, 1 H) 6.85-6.99 (m, 3 H) 7.21-7.31 (m, 2 H) 9.92-10.08 (m, 1 H). MS ESI/APCI Dual posi: 403[M + H]⁺. MS ESI/APCI Dual nega: 401[M − H]⁻. Na

TABLE 21-57 Compound Salt No. Structure Analytical Data information Example 1-392

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 2.40-2.50 (m, 2 H) 3.16-3.44 (m, 2 H) 3.48 (d, J = 4.5 Hz, 2 H) 4.50 (s, 2 H) 6.94-7.09 (m, 2 H) 7.15-7.29 (s, 2 H) 7.92- 7.95 (m, 1 H) 7.98-8.01 (m, 1 H). MS ESI/APCI Dual posi: 446[M + H]⁺. MS ESI/APCI Dual nega: 444[M − H]⁻. Na Example 1-393

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 2.40-2.50 (m, 2 H) 3.26-3.42 (m, 2 H) 3.43-3.52 (m, 2 H) 4.52 (s, 2 H) 6.99-7.10 (m, 2 H) 7.16-7.27 (m, 2 H) 7.69-7.79 (m, 1 H) 7.85-7.92 (m, 1 H). MS ESI/APCI Dual posi: 430[M + H]⁺. MS ESI/APCI Dual nega: 428[M − H]⁻. Na Example 1-394

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.31 (s, 3 H) 2.35 (s, 3 H) 2.51-2.53 (m, 2 H) 3.26-3.30 (m, 2 H) 3.48 (d, J = 4.5 Hz, 2 H) 4.48 (s, 2 H) 4.95 (s, 2 H) 7.21-7.25 (m, 2 H) 7.32-7.35 (m, 1 H). MS ESI/APCI Dual posi: 464[M + H]⁺. MS ESI/APCI Dual nega: 462[M − H]⁻. Na Example 1-395

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.30-1.40 (m, 1 H) 1.52- 1.62 (m, 1 H) 1.65-1.73 (m, 1 H) 1.74-1.82 (m, 1 H) 1.85- 1.94 (m, 1 H) 2.03-2.13 (m, 1 H) 2.44-2.57 (m, 3 H) 3.10-3.19 (m, 1 H) 3.26-3.48 (m, 6 H) 7.13-7.18 (m, 1 H) 7.22-7.32 (m, 4 H) 9.93-10.27 (m, 1 H). MS ESI/APCI Dual posi: 373[M + H]⁺. MS ESI/APCI Dual nega: 371[M − H]⁻. Na Example 1-396

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.29-0.41 (m, 2 H) 0.47- 0.55 (m, 2 H) 1.15 (s, 3 H) 2.39-2.54 (m, 2 H) 3.19-3.32 (m, 2 H) 3.45 (d, J = 4.4 Hz, 2 H) 4.02 (s, 2 H) 4.47 (s, 2 H) 6.75-6.84 (m, 1 H) 7.56-7.65 (m, 1 H) 8.01-8.08 (m, 1 H) 10.04 (br. s., 1 H). MS ESI/APCI Dual posi: 390[M + H]⁺. MS ESI/APCI Dual nega: 388[M − H]⁻. Na Example 1-397

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.04-0.14 (m, 2 H) 0.36- 0.47 (m, 2 H) 0.69-0.86 (m, 1 H) 1.53-1.66 (m, 2 H) 2.40- 2.50 (m, 2 H) 3.22-3.32 (m, 2 H) 3.48 (d, J = 4.5 Hz, 2 H) 4.21-4.32 (m, 2 H) 4.48 (s, 2 H) 6.72-6.81 (m, 1 H) 7.58- 7.65 (m, 1 H) 8.06-8.11 (m, 1 H) 10.07 (br. s., 1 H). MS ESI/APCI Dual posi: 390[M + H]⁺. MS ESI/APCI Dual nega: 388[M − H]⁻. Na Example 1-398

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.47 (s, 3 H) 2.48-2.54 (m, 2 H) 3.23-3.30 (m, 2 H) 3.49 (d, J = 4.4 Hz, 2 H) 4.49 (s, 2 H) 5.07 (s, 2 H) 6.95-7.02 (m, 2 H) 7.17-7.24 (m, 2 H) 7.27 (d, J = 7.8 Hz, 1 H) 7.74 (dd, J = 7.8, 2.2 Hz, 1 H) 8.51 (d, J = 2.2 Hz, 1 H) 9.91-10.17 (m, 1 H). MS ESI/APCI Dual posi: 426[M + H]⁺. MS ESI/APCI Dual nega: 424[M − H]⁻. Na

TABLE 21-58 Compound Salt No. Structure Analytical Data information Example 1-399

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.74-0.83 (m, 2 H) 0.87- 0.96 (m, 2 H) 2.19-2.35 (m, 2 H) 3.04-3.19 (m, 2 H) 3.45- 3.64 (m, 4 H) 7.13-7.41 (m, 5 H) 9.78-10.24 (m, 1 H). MS ESI/APCI Dual posi: 345[M + H]⁺. MS ESI/APCI Dual nega: 343[M − H]⁻. Na Example 1-400

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.73-0.83 (m, 2 H) 0.88- 0.97 (m, 2 H) 2.20-2.41 (m, 2 H) 3.07-3.25 (m, 2 H) 3.41- 3.65 (m, 4 H) 7.28-7.41 (m, 4 H) 9.75-10.21 (m, 1 H). MS ESI/APCI Dual posi: 379[M + H]⁺. MS ESI/APCI Dual nega: 377[M − H]⁻. Na Example 1-401

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.40-2.48 (m, 2 H) 2.48- 2.51 (m, 3 H) 3.21-3.29 (m, 2 H) 3.46 (d, J = 4.4 Hz, 2 H) 4.49 (s, 2 H) 5.11 (s, 2 H) 6.96-7.05 (m, 2 H) 7.18-7.28 (m, 3 H) 7.78 (dd, J = 7.6, 1.7 Hz, 1 H) 8.40 (dd, J = 4.8, 1.7 Hz, 1 H) 9.98-10.15 (m, 1 H) MS ESI/APCI Dual posi: 426[M + H]⁺. MS ESI/APCI Dual nega: 424[M − H]⁻. Na Example 1-402

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.99-1.42 (m, 4 H) 1.54- 1.80 (m, 3 H) 1.97-2.14 (m, 2 H) 2.40-2.63 (m, 2 H) 3.16- 3.52 (m, 6 H) 4.08-4.30 (m, 1 H) 6.84-7.16 (s, 4 H) 9.90-10.31 (m, 1 H). MS ESI/APCI Dual posi: 421[M + H]⁺. MS ESI/APCI Dual nega: 419[M − H]⁻. Na Example 1-403

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.06-1.44 (m, 4 H) 1.58- 1.83 (m, 3 H) 2.00-2.18 (m, 2 H) 2.40-2.63 (m, 2 H) 3.17- 3.52 (m, 6 H) 4.30-4.48 (m, 1 H) 7.06-7.20 (m, 2 H) 7.51-7.73 (m, 2 H) 9.91-10.14 (m, 1 H). MS ESI/APCI Dual posi: 471[M + H]⁺. MS ESI/APCI Dual nega: 469[M − H]⁻. Na Example 1-404

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.61-0.73 (m, 2 H) 0.89- 1.00 (m, 2 H) 1.83-1.99 (m, 1 H) 2.46-2.61 (m, 2 H) 3.26- 3.58 (m, 4 H) 4.55 (s, 2 H) 6.85-6.94 (m, 1 H) 7.00- 7.08 (m, 2 H) 7.23-7.35 (m, 2 H) 7.43-7.53 (m, 1 H) 7.93- 8.01 (m, 1 H) 10.01-10.19 (m, 1 H). MS ESI/APCI Dual posi: 438[M + H]⁺. Na Example 1-405

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.49-2.53 (m, 2 H) 3.27 (

, J = 7.1 Hz, 2 H) 3.50 (d, J = 4.4 Hz, 2 H) 4.49 (s, 2 H) 5.16 (s, 2 H) 6.94-7.03 (m, 2 H) 7.17-7.26 (m, 2 H) 7.56 (dd, J = 8.4, 0.6 Hz, 1 H) 7.97 (dd, J = 8.4, 2.5 Hz, 1 H) 8.63 (dd, J = 2.5, 0.6 Hz, 1 H) 9.97-10.17 (m, 1 H). MS ESI/APCI Dual posi: 446[M + H]⁺. MS ESI/APCI Dual nega: 444[M − H]⁻. Na

indicates data missing or illegible when filed

TABLE 21-59 Compound Salt No. Structure Analytical Data information Example 1-406

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.43 (d, J = 1.1 Hz, 3 H) 2.46-2.52 (m, 2 H) 3.22-3.31 (m, 2 H) 3.48 (d, J = 4.4 Hz, 2 H) 4.49 (s, 2 H) 5.32 (s, 2 H) 6.96-7.06 (m, 2 H) 7.17-7.26 (m, 2 H) 7.49 (q, J = 1.2 Hz, 1 H) 9.96-10.17 (m, 1 H). MS ESI/APCI Dual posi: 432[M + H]⁺. MS ESI/APCI Dual nega: 430[M − H]⁻. Na Example 1-407

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.42-2.49 (m, 2 H) 3.21- 3.28 (m, 2 H) 3.44 (d, J = 4.5 Hz, 2 H) 4.48 (s, 2 H) 5.02 (s, 2 H) 6.95-7.03 (m, 2 H) 7.16-7.23 (m, 2 H) 7.24 (d, J = 4.4 Hz, 1 H) 7.84 (s, 1 H) 7.89 (d, J = 4.4 Hz, 1 H) 9.94- 10.12 (m, 1 H). MS ESI/APCI Dual posi: 457[M + H]⁺. MS ESI/APCI Dual nega: 455[M − H]⁻. Na Example 1-408

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.32 (s, 3 H) 2.51-2.62 (m, 2 H) 3.32-3.40 (m, 2 H) 3.46 (d, J = 4.5 Hz, 2 H) 4.50 (s, 2 H) 7.02-7.10 (m, 2 H) 7.18-7.26 (m, 2 H) 8.56 (s, 2 H). Na Example 1-409

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.16 (

, J = 6.8 Hz, 2 H) 2.26 (s, 3 H) 2.40-2.50 (m, 2 H) 3.08 (

, J = 6.8 Hz, 2 H) 3.43 (d, J = 4.1 Hz, 2 H) 4.44 (s, 2 H) 7.07-7.15 (m, 2 H) 7.37- 7.45 (m, 2 H) 7.62 (d, J = 1.7 Hz, 1 H) 7.87 (d, J = 1.7 Hz, 1 H) 10.08 (t, J = 4.5 Hz, 1 H). MS ESI/APCI Dual posi: 446[M + H]⁺. MS ESI/APCI Dual nega: 444[M − H]⁻. Na Example 1-410

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.17 (s, 3 H) 2.45-2.58 (m, 2 H) 3.26-3.36 (m, 2 H) 3.48-3.55 (m, 2 H) 4.49 (s, 2 H) 4.89-5.06 (m, 2 H) 7.52-7.60 (m, 1 H) 7.91-8.01 (m, 1 H) 10.06 (br. s., 1 H). MS ESI/APCI Dual posi: 418[M + H]⁺. MS ESI/APCI Dual nega: 416[M − H]⁻. Na Example 1-411

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.05-0.16 (m, 2 H) 0.36- 0.48 (m, 2 H) 0.73-0.89 (m, 1 H) 1.55-1.67 (m, 2 H) 2.12 (s, 3 H) 2.42-2.54 (m, 2 H) 3.23-3.34 (m, 2 H) 3.43- 3.52 (m, 2 H) 4.23-4.35 (m, 2 H) 4.45 (s, 2 H) 7.41-7.47 (m, 1 H) 7.86-7.94 (m, 1 H) 10.04 (br. s., 1 H). MS ESI/APCI Dual posi: 404[M + H]⁺. MS ESI/APCI Dual nega: 402[M − H]⁻. Na Example 1-412

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.96-1.45 (m, 4 H) 1.55- 1.82 (m, 3 H) 1.99-2.17 (m, 2 H) 2.42-2.63 (m, 2 H) 3.11- 3.53 (m, 6 H) 4.71-4.93 (m, 1 H) 6.72-6.86 (m, 1 H) 7.56-7.73 (m, 1 H) 8.03-8.20 (m, 1 H) 9.90-10.31 (m, 1 H). MS ESI/APCI Dual posi: 422[M + H]⁺. MS ESI/APCI Dual nega: 420[M − H]⁻. Na

indicates data missing or illegible when filed

TABLE 21-60 Compound Salt No. Structure Analytical Data information Example 1-413

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.29 (s, 6 H) 2.15-2.31 (m, 2 H) 2.75-2.89 (m, 2 H) 3.39-3.52 (m, 4 H) 7.33- 7.42 (m, 2 H) 7.44-7.54 (m, 2 H) 9.89-10.14 (m, 1 H). MS ESI/APCI Dual posi: 381└M + H┘⁺. MS ESI/APCI Dual nega: 379└M − H┘⁻. Na Example 1-414

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.89-1.04 (m, 4 H) 2.05- 2.21 (m, 1 H) 2.42-2.61 (m, 2 H) 3.20-3.58 (m, 4 H) 4.61 (s, 2 H) 7.32-7.45 (m, 3 H) 7.59-7.71 (m, 2 H) 7.85- 7.96 (m, 1 H) 8.64-8.76 (m, 1 H) 10.00-10.23 (m, 1 H). MS ESI/APCI Dual posi: 422└M + H┘⁺. Na Example 1-415

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.38 (s, 3 H) 2.47-2.53 (m, 2 H) 3.31-3.38 (m, 2 H) 3.76 (d, J = 4.2 Hz, 2 H) 4.58 (s, 2 H) 5.12 (s, 2 H) 7.16 (d, J = 8.5 Hz, 1 H) 7.27-7.37 (m, 3 H) 7.39-7.46 (m, 2 H) 8.20 (d, J = 2.6 Hz, 1 H) 9.95- 10.10 (m, 1 H). MS ESI/APCI Dual posi: 426└M + H┘⁺. MS ESI/APCI Dual nega: 424└M − H┘⁻. Na Example 1-416

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.51-2.56 (m, 2 H) 3.25- 3.31 (m, 2 H) 3.43 (d, J = 4.5 Hz, 2 H) 4.56 (s, 2 H) 5.07 (s, 2 H) 6.88-7.05 (m, 3 H) 7.23-7.35 (m, 4 H) 7.42 (d, J = 8.2 Hz, 2 H). MS ESI/APCI Dual posi: 411└M + H┘⁺. MS ESI/APCI Dual nega: 409└M − H┘⁻. Na Example 1-417

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.22 (s, 3 H) 2.43-2.49 (m, 2 H) 3.25-3.30 (m, 2 H) 3.43 (d, J = 4.4 Hz, 2 H) 4.56 (s, 2 H) 5.03 (s, 2 H) 6.84-6.93 (m, 2 H) 7.03-7.12 (m, 2 H) 7.23-7.32 (m, 2 H) 7.35-7.45 (m, 2 H) 9.87-10.07 (m, 1 H). MS ESI/APCI Dual posi: 425└M + H┘⁺. MS ESI/APCI Dual nega: 423└M − H┘⁻. Na Example 1-418

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.30 (s, 3 H) 2.45-2.51 (m, 2 H) 3.26-3.33 (m, 2 H) 3.47 (d, J = 4.5 Hz, 2 H) 4.49 (s, 2 H) 5.27 (s, 2 H) 6.83 (dd, J = 8.5, 0.5 Hz, 1 H) 7.14- 7.20 (m, 2 H) 7.29-7.36 (m, 2 H) 7.64 (dd, J = 8.5, 2.4 Hz, 1 H) 8.07-8.14 (m, 1 H) 9.96-10.14 (m, 1 H). MS ESI/APCI Dual posi: 426└M + H┘⁺. MS ESI/APCI Dual nega: 424└M − H┘⁻. Na Example 1-419

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.45-2.50 (m, 2 H) 3.29- 3.38 (m, 2 H) 3.55 (d, J = 4.2 Hz, 2 H) 4.50 (s, 2 H) 5.33 (s, 2 H) 6.78-6.92 (m, 1 H) 7.38-7.51 (m, 4 H) 7.66 (dd, J = 8.5, 2.5 Hz, 1 H) 8.08-8.14 (m, 1 H) 9.88-10.07 (m, 1 H). MS ESI/APCI Dual posi: 446└M + H┘⁺. MS ESI/APCI Dual nega: 444└M − H┘⁻. Na

TABLE 21-61 Compound Salt No. Structure Analytical Data information Example 1-420

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.07-0.16 (m, 2 H) 0.34- 0.49 (m, 2 H) 0.72-0.91 (m, 1 H) 1.55-1.70 (m, 2 H) 2.43- 2.57 (m, 2 H) 3.27-3.39 (m, 2 H) 3.53-3.60 (m, 2 H) 4.32-4.42 (m, 2 H) 4.48 (s, 2 H) 7.77-7.82 (m, 1 H) 8.05- 8.09 (m, 1 H) 10.10 (br. s., 1 H). MS ESI/APCI Dual posi: 424└M + H┘⁺. MS ESI/APCI Dual nega: 422└M − H┘⁻. Na Example 1-421

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.46-2.58 (m, 2 H) 3.33 (t, J = 7.1 Hz, 2 H) 3.50 (d, J = 4.4 Hz, 2 H) 3.95 (s, 3 H) 4.62 (s, 2 H) 6.73-6.81 (m, 1 H) 7.34-7.44 (m, 2 H) 7.50- 7.58 (m, 1 H) 7.71-7.83 (m, 1 H) 8.00-8.11 (m, 2 H) 10.02-10.20 (m, 1 H). MS ESI/APCI Dual posi: 412└M + H┘⁺. Na Example 1-422

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.10-2.31 (m, 2 H) 3.12 (t, J = 6.3 Hz, 2 H) 3.47 (d, J = 4.4 Hz, 2 H) 4.59 (s, 2 H) 7.31-7.43 (m, 2 H) 7.91-8.08 (m, 4 H) 8.62-8.73 (m, 1 H) 10.14-10.25 (m, 1 H). MS ESI/APCI Dual posi: 416└M + H┘⁺. Na Example 1-423

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.51-2.59 (m, 2 H) 3.26 - 3.33 (m, 2 H) 3.46 (d, J = 4.4 Hz, 2 H) 4.58 (s, 2 H) 5.27 (s, 2 H) 7.28-7.36 (m, 2 H) 7.41-7.50 (m, 2 H) 7.68 (dd, J = 8.5, 2.7 Hz, 1 H) 7.80-7.91 (m, 1 H) 8.49-8.54 (m, 1 H) 9.89-10.11 (m, 1 H). MS ESI/APCI Dual posi: 480└M + H┘⁺. MS ESI/APCI Dual nega: 478└M − H┘⁻. Na Example 1-424

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.41-2.49 (m, 2 H) 3.23- 3.30 (m, 2 H) 3.47 (d, J = 4.4 Hz, 2 H) 4.56 (s, 2 H) 5.41 (s, 2 H) 7.03-7.12 (m, 1 H) 7.29 (d, J = 8.1 Hz, 2 H) 7.43 (d, J = 8.1 Hz, 2 H) 8.04-8.14 (m, 1 H) 8.57-8.64 (m, 1 H) 9.98-10.15 (m, 1 H). MS ESI/APCI Dual nega: 478└M − H┘⁻. Na Example 1-425

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.46-2.60 (m, 2 H) 3.33 (t, J = 7.0 Hz, 2 H) 3.54 (d, J = 4.5 Hz, 2 H) 3.87 (s, 3 H) 4.61 (s, 2 H) 7.27-7.40 (m, 2 H) 7.42-7.53 (m, 1 H) 7.83- 8.04 (m, 3 H) 8.31-8.44 (m, 1 H) 10.03-10.25 (m, 1 H). MS ESI/APCI Dual posi: 412└M + H┘⁺. Na Example 1-426

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.48-2.62 (m, 2 H) 3.34 (t, J = 7.1 Hz, 2 H) 3.58 (d, J = 4.5 Hz, 2 H) 3.84 (s, 3 H) 4.62 (s, 2 H) 7.29-7.42 (m, 3 H) 7.50-7.61 (m, 1 H) 7.81- 7.89 (m, 2 H) 8.21-8.31 (m, 1 H) 10.08-10.23 (m, 1 H). MS ESI/APCI Dual posi: 412└M + H┘⁺. Na

TABLE 21-62 Compound Salt No. Structure Analytical Data information Example 1-427

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.19-1.62 (m, 6 H) 1.60- 1.77 (m, 1 H) 1.78-1.93 (m, 2 H) 2.38-2.51 (m, 2 H) 3.14- 3.48 (m, 6 H) 3.53-3.63 (m, 1 H) 4.45 (s, 2 H) 7.31- 7.45 (m, 4 H) 9.87-10.22 (m, 1 H). MS ESI/APCI Dual posi: 451[M + H]⁺. MS ESI/APCI Dual nega: 449[M − H]⁻. Na Example 1-428

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.01-1.40 (m, 4 H) 1.65- 1.79 (m, 3 H) 1.99-2.13 (m, 2 H) 2.43-2.61 (m, 2 H) 3.15- 3.50 (m, 6 H) 4.17-4.33 (m, 1 H) 6.91-7.00 (m, 2 H) 7.24-7.33 (m, 2 H) 9.92-10.30 (m, 1 H). MS ESI/APCI Dual posi: 437[M + H]⁺. MS ESI/APCI Dual nega: 435[M − H]⁻. Na Example 1-429

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.85-1.27 (m, 4 H) 1.49- 1.74 (m, 3 H) 1.95-2.10 (m, 2 H) 2.42-2.61 (m, 2 H) 3.10- 3.48 (m, 7 H) 4.49 (s, 2 H) 7.29-7.43 (m, 4 H) 9.88- 10.31 (m, 1 H). MS ESI/APCI Dual posi: 451[M + H]⁺. MS ESI/APCI Dual nega: 449[M − H]⁻. Na Example 1-430

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00-1.40 (m, 4 H) 1.55- 1.79 (m, 3 H) 1.97-2.12 (m, 2 H) 2.21 (s, 3 H) 2.44-2.63 (m, 2 H) 3.15-3.50 (m, 6 H) 4.07-4.27 (m, 1 H) 5.76- 6.85 (m, 2 H) 6.99-7.10 (m, 2 H) 9.88-10.28 (m, 1 H). MS ESI/APCI Dual posi: 417[M + H]⁺. MS ESI/APCI Dual nega: 415[M − H]⁻. Na Example 1-431

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00-1.19 (m, 5 H) 1.20- 1.38 (m, 2 H) 1.55-1.79 (m, 3 H) 1.97-2.13 (m, 2 H) 2.44- 2.63 (m, 4 H) 3.15-3.50 (m, 6 H) 4.10-4.25 (m, 1 H) 6.76-6.87 (m, 2 H) 7.01-7.15 (m, 2 H) 9.85-10.16 (m, 1 H). MS ESI/APCI Dual posi: 431[M + H]⁺. MS ESI/APCI Dual nega: 429[M − H]⁻. Na Example 1-432

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.98-1.21 (m, 2 H) 1.25- 1.47 (m, 2 H) 1.57-1.83 (m, 3 H) l.98-2-17 (m, 2 H) 2.43 2.62 (m, 2 H) 3.14-3.48 (m, 6 H) 4.75-4.95 (m, 1 H) 6.81 (d, J = 8.9 Hz, 1 H) 7.76 (dd, J = 8.9, 2.6 Hz, 1 H) 8.19 (d, J = 2.6 Hz, 1 H) 9.88-10.27 (m, 1 H). MS ESI/APCI Dual posi: 438[M + H]⁺. MS ESI/APCI Dual nega: 436[M − H]⁻ _(.) Na Example 1-433

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.22-1.97 (m, 9 H) 2.43- 2.70 (m, 2 H) 3.18-3.51 (m, 4 H) 3.70-3.86 (m, 2 H) 5.04- 5.18 (m, 1 H) 6.81-6.93 (m, 1 H) 7.57-7.72 (m, 1 H) 8.06-8.15 (m, 1 H) 9.98-10.25 (m, 1 H). MS ESI/APCI Dual posi: 422[M + H]⁺. Na

TABLE 21-63 Compound Salt No. Structure Analytical Data information Example 1-434

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.22-1.62 (m, 6 H) 1.65- 1.95 (m, 3 H) 2.25-2.49 (m, 2 H) 3.16-3.47 (m, 6 H) 4.44- 4.57 (m, 1 H) 6.90-7.00 (m, 2 H) 7.03-7.15 (m, 2 H) 9.94-10.17 (m, l H). MS ESI/APCI Dual posi: 421[M + H]⁺. Na Example 1-435

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.98-1.20 (m, 2 H) 1.23- 1.43 (m, 2 H) 1.56-1.80 (m, 3 H) 1.98-2.13 (m, 2 H) 2.18 (s, 3 H) 2.45-2.67 (m, 2 H) 3.15-3.50 (m, 6 H) 4.74- 4.96 (m, 1 H) 6.64 (d, J = 8.4 Hz, 1 H) 7.48 (dd, J = 8.4, 2.0 Hz, 1 H) 7.89-7.99 (m, 1 H) 9.86-10.31 (m, 1 H). MS ESI/APCI Dual posi: 418[M + H]⁺. MS ESI/APCI Dual nega: 416[M − H]⁻ _(.) Na Example 1-436

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.43-2.62 (m, 2 H) 3.31 (

, J = 6.9 Hz, 2 H) 3.53 (d, J = 4.4 Hz, 2 H) 3.90 (s, 3 H) 4.62 (s, 2 H) 6.89-7.01 (m, 1 H) 7.29-7.54 (m, 3 H) 7.99- 8.14 (m, 2 H) 8.41-8.55 (m, 1 H) 10.06-10.24 (m, 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺. Na Example 1-437

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.00-1.24 (m, 2 H) 1.30- 1.52 (m, 2 H) 1.58-1.85 (m, 3 H) 2.04-2.18 (m, 2 H) 2.44- 2.60 (m, 2 H) 3.16-3.56 (m, 6 H) 4.91-5-12 (m, 1 H) 6.89- 7.00 (m, 1 H) 7.95-8.11 (m, 1 H) 8.50-8.67 (m, 1 H) 9.99-10.21 (m, 1 H). MS ESI/APCI Dual posi: 472[M + H]⁺. Na Example 1-438

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.85-1.26 (m, 4 H) 1.49- 1.76 (m, 3 H) 1.94-2.11 (m, 2 H) 2.42-2.60 (m, 2 H) 3.12- 3.48 (m, 7 H) 4.47 (s, 2 H) 7.08-7.21 (m, 2 H) 7.29- 7.41 (m, 2 H) 9.87-10.23 (m, 1 H). MS ESI/APCI Dual posi: 435[M + H]⁺. MS ESI/APCI Dual nega: 433[M − H]⁻ _(.) Na Example 1-439

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.98-1.21 (m, 2 H) 1.26- 1.45 (m, 2 H) 1.58-1.82 (m, 3 H) 2.03-2.17 (m, 2 H) 2.44- 2.66 (m, 2 H) 3.14-3.55 (m, 6 H) 4.83-5.00 (m, 1 H) 6.67-6.79 (m, 1 H) 6.87-7.03 (m, 1 H) 7.59-7.73 (m, 1 H) 8.08-8.20 (m, 1 H) 9.88-10.33 (m, 1 H). MS ESI/APCI Dual posi: 404[M + H]⁺. Na Example 1-440

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.51-2.67 (m, 2 H) 3.41- 3.59 (m, 4 H) 4.57-4.74 (m, 2 H) 7.18-7.34 (m, 2 H) 7.40- 7.57 (m, 2 H) 8.14 (s, 1 H) 8.49 (s, 1 H) 10.00 (br. s., 1 H). MS ESI/APCI Dual posi: 433[M + H]⁺. MS ESI/APCI Dual nega: 431[M − H]⁻ _(.) Na

indicates data missing or illegible when filed

TABLE 21-64 Compound Salt No. Structure Analytical Data information Example 1-441

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.06-0.16 (m, 2 H) 0.38- 0.50 (m, 2 H) 0.72-0.90 (m, 1 H) 1.62 (q, J = 6.6 Hz, 2 H) 2.51-2.62 (m, 2 H) 3.36-3.43 (m, 2 H) 3.46 (d, J = 4.4 Hz, 2 H) 4.07 (

, J = 6.6 Hz, 2 H) 4.58 (s, 2 H) 7.22 (d, J = 8.5 Hz, 1 H) 7.36 (dd, J = 8.5, 3.0 Hz, 1 H) 8.21 (d, J = 3.0 Hz, 1 H) 9.90-10.10 (m, 1 H). MS ESI/APCI Dual posi: 390[M + H]⁺. MS ESI/APCI Dual nega: 388[M − H]⁻ _(.) Na Example 1-442

¹H NMR(300 MHz, DMSO-d₆) δ ppm 0.46-0.63 (m, 2 H) 0.78- 0.93 (m, 2 H) l.00-1.39 (m, 4 H) 1.55-1.76 (m, 3 H) 1.76- 1.90 (m, 1 H) 1.96-2.12 (m, 1 H) 2.44-2.60 (m, 2 H) 3.15-3.49 (m, 6 H) 4.08-4.25 (m, 1 H) 6.74-6.85 (m, 2 H) 6.91-7.01 (m, 2 H) 9.89-10.29 (m, 1 H). MS ESI/APCI Dual posi: 443[M + H]⁺. MS ESI/APCI Dual nega: 441[M − H]⁻ _(.) Na Example 1-443

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.60-0.73 (m, 2 H) 0.88- 1.01 (m, 2 H) 1.85-2.02 (m, 1 H) 2.50-2.66 (m, 2 H) 3.40- 3.59 (m, 4 H) 4.64 (s, 2 H) 7.01-7.19 (m, 4 H) 8.12 (d, J = 1.4 Hz, 1 H) 8.44 (d, J = 1.4 Hz, 1 H) 9.84-10.18 (m, 1 H). MS ESI/APCI Dual posi: 439[M + H]⁺. MS ESI/APCI Dual nega: 437[M − H]⁻. Na Example 1-444

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.86-1.05 (m, 2 H) 1.07- 1.26 (m, 2 H) 1.50- l.75 (m, 3 H) 1.97-2.11 (m, 2 H) 2.46- 2.54 (m, 2 H) 3.13-3.48 (m, 7 H) 4.49 (s, 2 H) 7.21- 7.39 (m, 5 H) 9.90-10.24 (m, 1 H). MS ESI/APCI Dual posi: 417[M + H]⁺. MS ESI/APCI Dual nega: 415[M − H]⁻. Na Example 1-445

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.07-0.17 (m, 2 H) 0.37- 0.48 (m, 2 H) 0.85-1.16 (m, 5 H) 1.46-1.72 (m, 3 H) 1.88- 2.03 (m, 2 H) 2.43-2.59 (m, 2 H) 3.09-3.48 (m, 9 H) 9.84-10.21 (m, 1 H). MS ESI/APCI Dual posi: 381[M + H]⁺. MS ESI/APCI Dual nega: 379[M − H]⁻. Na Example 1-446

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.51-0.59 (m, 2 H) 0.81- 0.96 (m, 2 H) 0.99-1.43 (m, 4 H) 1.55-1.94 (m, 4 H) 1.98- 2.15 (m, 2 H) 2.37-2.52 (m, 2 H) 3.15-3.56 (m, 6 H) 4.74-4.95 (m, 1 H) 6.67-6.72 (m, 1 H) 7.26-7.37 (m, 1 H) 7.91-8.00 (m, 1 H) 10.02-10.21 (m, 1 H). MS ESI/APCI Dual posi: 444[M + H]⁺. Na Example 1-447

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.86-0.99 (m, 2 H) 1.01- 1.13 (m, 2 H) 1.50-1.69 (m, 3 H) 1.91-2.00 (m, 2 H) 2.45 2.59 (m, 2 H) 2.76 (t, J = 7.2 Hz, 2 H) 3.10-3.22 (m, 3 H) 3.25-3.47 (m, 4 H) 3.60 (t, J = 7.2 Hz, 2 H) 7.14-7.32 (m, 5 H) 9.89-10.26 (m, 1 H). MS ESI/APCI Dual posi: 431[M + H]⁺. MS ESI/APCI Dual nega: 429[M − H]⁻. Na

indicates data missing or illegible when filed

TABLE 21-65 Compound Salt No. Structure Analytical Data information Example 1-448

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.87-1.00 (m, 2 H) 1.02- 1.12 (m, 2 H) 1.13-1.22 (m, 2 H) 1.41-1.70 (m,

 H) 1.90- 2.06 (m, 3 H) 2.47-2.58 (m, 2 H) 3.07-3.21 (m, 3 H) 3.25 (d, J = 7.0 Hz, 2 H) 3.27-3.48 (m, 4 H) 9.91-10.25 (m, 1 H). MS ESI/APCI Dual posi: 409[M + H]⁺. MS ESI/APCI Dual nega: 407[M − H]⁻. Na Example 1-449

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.04-1.18 (m, 5 H) 1.27- 1.38 (m, 2 H) 1.61-1.77 (m, 3 H) 2.02-2.12 (m, 2 H) 2.45- 2.60 (m, 4 H) 3.14-3.49 (m, 5 H) 4.81-4.90 (m, 1 H) 6.66 (d, J = 8.3 Hz, 1 H) 7.52 (dd, J = 8.3, 2.5 Hz, 1 H) 7.96 (d, J = 2.5 Hz, 1 H) 9.91-10.28 (m, 1 H). MS ESI/APCI Dual posi: 432[M + H]⁺. MS ESI/APCI Dual nega: 430[M − H]⁻. Na Example 1-450

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.86-1.01 (m, 2 H) 1.08- 1.21 (m, 2 H) 1.53-1.74 (m, 3 H) 1.97-2.06 (m, 2 H) 2.38 (s, 3 H) 2.45-2.59 (m, 2 H) 3.11-3.48 (m, 7 H) 4.44 (s, 2 H) 7.10-7.15 (m, 2 H) 7.17-7.22 (m, 2 H) 9.89-10.29 (m, 1 H). MS ESI/APCI Dual posi: 431[M + H]⁺. MS ESI/APCI Dual nega: 429[M − H]⁻. Na Example 1-451

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.87-0.99 (m, 2 H) 1.03- 1.14 (m, 2 H) 1.33-1.47 (m, 1 H) 1.49-1.67 (m, 4 H) 1.74- 1.84 (m, 2 H) 1.85-1.93 (m, 2 H) 2.06-2.17 (m, 2 H) 2.46-2.56 (m, 2 H) 3.09-3.21 (m, 3 H) 3.25-3.50 (m, 4 H) 3.93-4.02 (m, 1 H) 9.89-10.27 (m, 1 H). MS ESI/APCI Dual posi: 381[M + H]⁺. MS ESI/APCI Dual nega: 379[M − H]⁻. Na Example 1-452

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.07 (d, J = 6.7 Hz, 3 H) 2.15- 2.30 (m, 2 H) 2.68-2.85 (m, 2 H) 3.10-3.26 (m, 2 H) 3.35-3.46 (m, 2 H) 4.74-4.91 (m, 1 H) 7.19-7.27 (m, 2 H) 7.28-7.36 (m, 2 H) 9.91-10.09 (m, 1 H). MS ESI/APCI Dual posi: 367[M + H]⁺. MS ESI/APCI Dual nega: 365[M − H]⁻. Na Example 1-453

¹H NMR (300 MHz, METHANOL-d₄) δ ppm 1.24-1.56 (m, 5 H) 1.70-1.91 (m, 5 H) 2.51-2.62 (m, 2 H) 2.76-2.91 (m, 1 H) 3.33-3.40 (m, 2 H) 3.89 (s, 2 H) 4.58 (s, 2 H) 6.92- 7.01 (m, 1 H) 7.02-7.09 (m, 1 H) 7.18-7.28 (m, 1 H). MS ESI/APCI Dual posi: 405[M + H]⁺. MS ESI/APCI Dual nega: 403[M − H]⁻. Na Example 1-454

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.04-2.19 (m, 2 H) 2.20- 2.32 (m, 2 H) 2.40-2.78 (m, 3 H) 3.04-3.67 (m, 6 H) 4.62- 5.03 (m, 1 H) 4.84 (quin, J = 6.3 Hz, 1 H) 6.61-7.03 (m, 2 H) 7.16-7.46 (m, 2 H) 9.87-10.27 (m, 1 H). MS ESI/APCI Dual posi: 409[M + H]⁺. MS ESI/APCI Dual nega: 407[M − H]⁻. Na

indicates data missing or illegible when filed

TABLE 21-66 Compound Salt No. Structure Analytical Data information Example 1-455

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.53-1.69 (m, 2 H) 1.95- 2.11 (m, 1 H) 2.20-2.37 (m, 2 H) 2.44-2.58 (m, 2 H) 3.25- 3.44 (m, 4 H) 3.46-3.56 (m, 2 H) 3.75-3.92 (m, 1 H) 4.34 (s, 2 H) 7.24-7.50 (m, 4 H). MS ESI/APCI Dual posi: 423[M + H]⁺. MS ESI/APCI Dual nega: 421[M − H]⁻. Na Example 1-456

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.66-1.88 (m, 2 H) 2.10- 2.32 (m, 1 H) 2.47-2.65 (m, 2 H) 3.29-3.52 (m, 8 H) 4.43- 4.65 (m, 1 H) 6.76-6.95 (m, 2 H) 7.23-7.37 (m, 2 H). MS ESI/APCI Dual posi: 409[M + H]⁺. MS ESI/APCI Dual nega: 407[M − H]⁻. Na Example 1-457

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.92-2.08 (m, 4 H) 2.44- 2.59 (m, 3 H) 3.33-3.51 (m, 6 H) 4.10-4.25 (m, 1 H) 4.35 (s, 2 H) 7.22-7.54 (m, 4 H). MS ESI/APCI Dual posi: 423[M + H]⁺. MS ESI/APCI Dual nega: 421[M − H]⁻. Na Example 1-458

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.04-2.16 (m, 2 H) 2.18- 2.29 (m, 5 H) 2.47-2.66 (m, 3 H) 3.34-3.57 (m, 6 H) 4.75- 4.84 (m, 1 H) 6.65-6.74 (m, 2 H) 7.02-7.09 (m, 2 H). MS ESI/APCI Dual posi: 389[M + H]⁺. MS ESI/APCI Dual nega: 387[M − H]⁻. Na Example 1-459

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.10-2.23 (m, 2 H) 2.25- 2.37 (m, 2 H) 2.48-2.71 (m, 2 H) 3.33-3.45 (m, 2 H) 3.47- 3.61 (m, 4 H) 4.89-5.00 (m, 1 H) 7.00 (d, J = 8.7 Hz, 2 H) 7.63 (d, J = 8.7 Hz, 2 H). MS ESI/APCI Dual posi: 443[M + H]⁺. MS ESI/APCI Dual nega: 441[M − H]⁻. Na Example 1-460

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.06-2.20 (m, 2 H) 2.20- 2.35 (m, 2 H) 2.40-2.72 (m, 3 H) 3.33-3.58 (m, 6 H) 4.83- 4.97 (m, 1 H) 6.77-6.85 (m, 1 H) 6.86-6.92 (m, 1 H) 6.94-7.03 (m, 1 H) 7.24-7.35 (m, 1 H). MS ESI/APCI Dual posi: 409[M + H]⁺. MS ESI/APCI Dual nega: 407[M − H]⁻. Na Example 1-461

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.42-2.49 (m, 2 H) 3.19- 3.27 (m, 2 H) 3.43 (d, J = 4.4 Hz, 2 H) 4.47 (s, 2 H) 6.75 (s, 2 H) 7.04-7.14 (m, 2 H) 7.18-7.27 (m, 2 H) 7.41-7.50 (m, 1 H) 7.57-7.56 (m, 1 H) 7.87-7.96 (m, 1 H) 8.05- 8.12 (m, 1 H) 9.91-10.09 (m, 1 H). MS ESI/APCI Dual posi: 452[M + H]⁺, 474[M + Na]⁺. MS ESI/APCI Dual nega: 450[M − H]⁻. Na

TABLE 21-67 Compound Salt No. Structure Analytical Data information Example 1-462

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.10 (s, 3 H) 2.21-2.23 (m, 3 H) 2.48-2.54 (m, 2 H) 3.22-3.29 (m, 2 H) 3.44 (d, J = 4.4 Hz, 2 H) 4.49 (s, 2 H) 5.88 (s, 2 H) 5.90 (s, 1 H) 7.01-7.10 (m, 2 H) 7.17-7.26 (m, 2 H) 9.91-10.09 (m, 1 H). MS ESI/APCI Dual posi: 429[M + H]⁺. MS ESI/APCI Dual nega: 427[M − H]⁻. Na Example 1-463

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.41-2.48 (m, 2 H) 3.20- 3.28 (m, 2 H) 3.46 (d, J = 4.4 Hz, 2 H) 4.18 (s, 3 H) 4.49 (s, 2 H) 5.57 (s, 2 H) 7.02-7.13 (m, 3 H) 7.18-7.28 (m, 3 H) 7.52-7.63 (m, 1 H) 7.77-7.87 (m, 1 H) 9.96-10.15 (m, 1 H). MS ESI/APCI Dual posi: 465[M + H]⁺. MS ESI/APCI Dual nega: 463[M − H]⁻. Na Example 1-464

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.86-1.30 (m, 4 H) 1.49- 1.78 (m, 3 H) 1.97-2.13 (m, 2 H) 2.43-2.58 (m, 2 H) 3.13- 3.48 (m, 7 H) 4.57 (s, 2 H) 7.40-7.52 (m, 1 H) 7.86- 7.97 (m, 1 H) 8.48-8.61 (m, 1 H) 9.88-10.26 (m, 1 H). MS ESI/APCI Dual posi: 452[M + H]⁺. MS ESI/APCI Dual nega: 460[M − H]⁻. Na

Example 1-465 N-{[1-(4-Biphenylylmethyl)-6-(chloromethyl)-4-hydroxy-6-(hydroxymethyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine

The compound (1.70 g) obtained in Example 1-20) was used and treated by the same technique as in Example 1-1(4) to give the titled compound as a pale brown amorphous mass (363 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.61-3.08 (m, 2H) 3.45-3.66 (m, 2H) 3.70-3.93 (m, 2H) 3.96-4.10 (m, 2H) 4.69-4.90 (m, 2H) 5.46 (br. s., 1H) 7.28-7.51 (m, 5H) 7.54-7.70 (m, 4H) 9.89-10.31 (m, 1H) 12.73-13.04 (m, 1H).

MS ESI/APCI Dual posi: 459 [M+H]⁺.

Example 1-466 N-{[1-(3-Chloro-4-hydroxybenzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine disodium

(1) Synthesis of 2-methyl-2-propanyl N-[(1-{3-chloro-4-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]benzyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycinate

Instead of the compound obtained in Reference Example A-1, the compound (1.36 g) obtained in Reference Example A-301 was used and treated by the same techniques as in Example 1-1(1) to (3) to give 2-methyl-2-propanyl N-[(1-{3-chloro-4-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]benzyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycinate as a pale yellow gum (1.07 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.32 (s, 3H) 2.41 (s, 3H) 2.51-2.66 (m, 2H) 3.27-3.39 (m, 2H) 4.01-4.06 (m, 2H) 4.54 (s, 2H) 4.84-4.88 (m, 2H) 6.90-6.97 (m, 1H) 7.16 (dd, 2.2 Hz, 1H) 7.29-7.34 (m, 1H) 10.13-10.51 (m, 1H).

MS ESI/APCI Dual posi: 520 [M+H]⁺, 542 [M+Na]⁺.

MS ESI/APCI Dual nega: 518 [M−H]⁻.

(2) Synthesis of the Titled Compound

The compound (1.07 g) obtained in step (1) above was used and treated by the same techniques as in Example 1-1(4) and Example 1-3(3) to give the titled compound as a colorless solid (454 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.12-2.22 (m, 2H) 3.02-3.10 (m, 2H) 3.46 (d, J=4.2 Hz, 2H) 4.37 (s, 2H) 6.85 (d, J=8.4 Hz, 1H) 6.96 (dd, J=8.4, 2.0 Hz, 1H) 7.12 (d, J=2.0 Hz, 1H) 10.04-10.16 (m, 1H).

MS ESI/APCI Dual posi: 355 [M+H]⁺.

MS ESI/APCI Dual nega: 353[M−H]⁻.

Example 1-467 N-({1-[4-(4,4-difluoro-1-cyclohexen-1-yl)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine sodium salt

(1) Synthesis of 2-methyl-2-propanyl N-({1-[4-(4,4-difluoro-1-hydroxycyclohexyl)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate

Instead of the compound obtained in Reference Example A-1, the compound (583 mg) obtained in Reference Example B-18 was used and treated by the same techniques as in Examples 1-1(1) to (3) to give 2-methyl-2-propanyl N-({1-[4-(4,4-difluoro-1-hydroxycyclohexyl)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate as a colorless solid (226 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 1.82-1.94 (m, 2H) 2.07-2.42 (m, 6H) 2.62 (s, 2H) 3.30-3.39 (m, 2H) 4.01-4.06 (m, 2H) 4.61 (s, 2H) 7.25-7.30 (m, 2H) 7.43-7.50 (m, 2H).

MS ESI/APCI Dual posi: 517 [M+Na]⁺.

MS ESI/APCI Dual nega: 493 [M−H]⁻, 529 [M+Cl]⁻.

(2) Synthesis of the Titled Compound

The compound (226 mg) obtained in step (1) above was used and treated by the same techniques as in Example 1-1(4) and Example 1-3(3) to give the titled compound as a colorless solid (129 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.04-2.30 (m, 4H) 2.59-2.80 (m, 4H) 3.24-3.32 (m, 2H) 3.47 (d, J=4.4 Hz, 2H) 4.55 (s, 2H) 5.95-6.04 (m, 1H) 7.25 (d, J=8.3 Hz, 2H) 7.41 (d, J=8.3 Hz, 2H).

MS ESI/APCI Dual posi: 421 [M+H]⁺.

MS ESI/APCI Dual nega: 419 [M−H]⁻.

Example 1-468 N-({1-[4-(Cyclopropylmethoxy)-3-methylbenzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine sodium salt

(1) Synthesis of ethyl N-({1-[4-(cyclopropylmethoxy)-3-methylbenzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate

Instead of the compound obtained in Reference Example A-1 and glycine tert-butyl hydrochloride, the compound (2.10 g) obtained in Reference Example A-302 and glycine ethyl hydrochloride (956 mg) were respectively used and treated by the same techniques as in Example 1-1(1) to (3) to give ethyl N-({1-[4-(cyclopropylmethoxy)-3-methylbenzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate as a yellow oil (2.01 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.29-0.40 (m, 2H) 0.54-0.68 (m, 2H) 1.19-1.37 (m, 4H) 2.16-2.26 (m, 3H) 2.44-2.64 (m, 2H) 3.23-3.35 (m, 2H) 3.75-3.85 (m, 2H) 4.05-4.17 (m, 2H) 4.24 (q, J=7.1 Hz, 2H) 4.47-4.54 (m, 2H) 6.67-6.79 (m, 1H) 6.98-7.08 (m, 2H) 10.11-10.60 (m, 1H).

MS ESI/APCI Dual posi: 417 [M+H]⁺.

(2) Synthesis of the Titled Compound

To a solution in ethanol (37.8 mL) of the compound (1.97 g) obtained in step (1) above, 0.5 mol/L sodium hydroxide in aqueous solution (18.9 mL) was added under cooling with ice and the mixture was brought to room temperature at which it was stirred for 15 minutes. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by DIAION (registered trademark) HP20 column chromatography (with elution by methanol). The eluted fraction was concentrated under reduced pressure and to a solution of the resulting compound in water (2 mL), acetone (100 mL) was added and the mixture was stirred at room temperature for an hour. The precipitate was recovered by filtration to give the titled compound as a colorless solid (1.60 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.25-0.38 (m, 2H) 0.47-0.61 (m, 2H) 1.11-1.28 (m, 1H) 2.13 (s, 3H) 2.34-2.50 (m, 2H) 3.15-3.29 (m, 2H) 3.51 (d, J=4.5 Hz, 2H) 3.73-3.86 (m, 2H) 4.44 (s, 2H) 6.84 (d, J=9.0 Hz, 1H) 7.00-7.06 (m, 2H) 10.12 (br. s., 1H).

MS ESI/APCI Dual posi: 389 [M+H]⁺.

MS ESI/APCI Dual nega: 387[M−H]⁻.

Example 2-1 N-({4-Hydroxy-1-[(4′-methylbiphenyl-4-yl)methyl]-2-oxo-1,2,5,6-tetrahydropyridin-3-yl}carbonyl)glycine

(1) Synthesis of tert-butyl N-{[4-hydroxy-1-(4-iodobenzyl)-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycinate

Instead of the compound obtained in Reference Example A-1, the compound (6.50 g) obtained in Reference Example A-4 was used and treated by the same techniques as in Example 1-1(1) to (3) to give tert-butyl N-{[4-hydroxy-1-(4-iodobenzyl)-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycinate as a colorless solid (7.01 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9H) 2.49-2.65 (m, 2H) 3.24-3.42 (m, 2H) 3.97-4.08 (m, 2H) 4.56 (s, 2H) 6.98-7.08 (m, 2H) 7.57-7.75 (m, 2H) 10.13-10.51 (m, 1H).

MS ESI/APCI Dual posi: 487 [M+H]⁺.

MS ESI/APCI Dual nega: 485 [M−H]⁺.

(2) Synthesis of tert-butyl N-({4-hydroxy-1-[(4′-methylbiphenyl-4-yl)methyl]-2-oxo-1,2,5,6-tetrahydropyridin-3-yl}carbonyl)glycinate

A mixture of the compound (300 mg) obtained in step (1) above, 4-methylphenylboronic acid (168 mg), palladium(II) acetate (6.93 mg), tri(2-methylphenyl)phosphine (18.8 mg), tripotassium phosphate (393 mg), ethanol (8.00 mL) and toluene (4.00 mL) was stirred at 90° C. for an hour. After cooling the reaction mixture to room temperature, a saturated aqueous solution of ammonium chloride was added and the resulting mixture was concentrated under reduced pressure. Water was added and three extractions were conducted with chloroform. The combined organic layers were passed through a phase separator and thereafter concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-50:50, then chloroform:methanol=100:0-90:10) to give tert-butyl N-({4-hydroxy-1-[(4′-methylbiphenyl-4-yl)methyl]-2-oxo-1,2,5,6-tetrahydropyridin-3-yl}carbonyl)glycinate as a pale yellow solid (485 mg).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.39 (s, 3H) 2.53-2.65 (m, 2H) 3.37 (m, 2H) 4.00-4.08 (m, 2H) 4.66 (s, 2H) 7.25 (d, J=7.8 Hz, 2H) 7.32 (d, J=7.8 Hz, 2H) 7.44-7.50 (m, 2H) 7.51-7.58 (m, 2H) 10.22-10.49 (m, 1H).

MS ESI/APCI Dual posi: 473 [M+Na]⁺.

(3) Synthesis of the Titled Compound

The compound (147 mg) obtained in step (2) above was used and treated by the same technique as in Example 1-1(4) to give the titled compound as a colorless solid (111 mg).

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.33 (s, 3H) 2.46-2.72 (m, 2H) 3.36-3.46 (m, 2H) 3.98-4.07 (m, 2H) 4.57-4.67 (m, 2H) 7.23-7.29 (m, 2H) 7.32-7.40 (m, 2H) 7.50-7.57 (m, 2H) 7.58-7.65 (m, 2H) 10.01-10.25 (m, 1H).

MS ESI/APCI Dual posi: 395 [M+1]⁺, 417 [M+Na]⁺.

MS ESI/APCI Dual nega: 393 [M-1]⁻.

Example 2-2 N-({4-Hydroxy-1-[4-(3-methoxy-4-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine sodium salt

(1) Synthesis of 2-methyl-2-propanyl N-({4-hydroxy-1-[4-(3-methoxy-4-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate

A mixture of the compound (1.50 g) obtained in Example 2-1(1), 3-methoxy-4-pyridineboronic acid pinacol ester (870 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (1:1) (126 mg), 2 mol/L sodium carbonate in aqueous solution (3.4 mL) and N,N-dimethylformamide (12.3 mL) was stirred at 120° C. for 20 minutes under irradiation with microwaves. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added and the precipitate was recovered by filtration through Celite (registered trademark). Extraction was conducted with ethyl acetate and the combined organic layers were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:80-0:100, then chloroform:methanol=100:0-80:20) to give 2-methyl-2-propanyl N-({4-hydroxy-1-[4-(3-methoxy-4-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate as a yellow amorphous mass (1.24 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.52-2.69 (m, 2H) 3.32-3.45 (m, 2H) 3.92 (s, 3H) 4.00-4.07 (m, 2H) 4.67 (s, 2H) 7.22-7.26 (m, 2H) 7.32-7.38 (m, 2H) 7.50-7.60 (m, 2H) 8.28-8.35 (m, 1H) 10.18-10.50 (m, 1H).

MS ESI/APCI Dual posi: 468 [M+H]⁺.

(2) Synthesis of the Titled Compound

The compound (1.24 g) obtained in step (1) above was used and treated by the same techniques as in Example 1-2(2) and Example 1-3(3) to give the titled compound as a colorless solid (730 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.46-2.61 (m, 2H) 3.35 (t, J=7.1 Hz, 2H) 3.56 (d, J=4.5 Hz, 2H) 3.89 (s, 3H) 4.61 (s, 2H) 7.29-7.44 (m, 3H) 7.50-7.60 (m, 2H) 8.22-8.33 (m, 1H) 8.45 (s, 1H) 10.08-10.21 (m, 1H).

MS ESI/APCI Dual posi: 412[M+H]⁺.

Example 2-3 N-({4-Hydroxy-1-[4-(2-methoxy-3-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine sodium salt

(1) Synthesis of 2-methyl-2-propanyl N-({4-hydroxy-1-[4-(2-methoxy-3-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate

A mixture of the compound (1.00 g) obtained in Example 2-1(1), 2-methoxypyridine-3-boronic acid (426 mg), palladium(II) acetate (25.0 mg), tripotassium phosphate (987 mg) and ethylene glycol (12 mL) was stirred in a sealed tube at 80° C. for 4 hours. After cooling the reaction mixture to room temperature, water and ethyl acetate were added and the precipitate was recovered by filtration through Celite (registered trademark). Extraction was conducted with ethyl acetate and the combined organic layers were concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-20:80) to give 2-methyl-2-propanyl N-({4-hydroxy-1-[4-(2-methoxy-3-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate as a yellow oil (1.10 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.52-2.68 (m, 2H) 3.33-3.42 (m, 2H) 3.97 (s, 3H) 4.00-4.08 (m, 2H) 4.66 (s, 2H) 6.93-7.01 (m, 1H) 7.29-7.36 (m, 2H) 7.46-7.65 (m, 3H) 8.09-8.21 (m, 1H) 10.15-10.53 (m, 1H).

MS ESI/APCI Dual posi: 490 [M+Na]⁺

MS ESI/APCI Dual nega: 466[M−H]⁻.

(2) Synthesis of the Titled Compound

The compound (1.10 g) obtained in step (1) above was used and treated by the same techniques as in Example 1-2(2) and Example 1-3(3) to give the titled compound as a colorless solid (461 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.41-2.61 (m, 2H) 3.40-3.49 (m, 2H) 3.87 (s, 3H) 4.60 (s, 2H) 7.05-7.12 (m, 1H) 7.29-7.39 (m, 2H) 7.48-7.57 (m, 2H) 7.70-7.77 (m, 1H) 8.13-8.20 (m, 1H).

MS ESI/APCI Dual posi: 412 [M+H]⁺.

MS ESI/APCI Dual nega: 410[M−H]⁻.

Example 2-4 N-({4-Hydroxy-1-[4-(6-methyl-3-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine sodium salt

(1) Synthesis of 2-methyl-2-propanyl N-({4-hydroxy-1-[4-(6-methyl-3-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate

A mixture of the compound (1.00 g) obtained in Example 2-1(1), 2-picoline-5-boronic acid pinacol ester (541 mg), tetrakis(triphenylphosphine)palladium(0) (238 mg), potassium carbonate (569 mg), toluene (10 mL), ethanol (2 mL) and water (2 mL) was stirred at 80° C. for 4 hours. After cooling the reaction mixture to room temperature, the precipitate was removed by passage through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-30:70) to give 2-methyl-2-propanyl N-({4-hydroxy-1-[4-(6-methyl-3-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate (560 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.51-2.69 (m, 5H) 3.31-3.44 (m, 2H) 4.00-4.07 (m, 2H) 4.67 (s, 2H) 7.17-7.26 (m, 1H) 7.37 (d, J=8.2 Hz, 2H) 7.48-7.59 (m, 2H) 7.72-7.81 (m, 1H) 8.67-8.77 (m, 1H) 10.15-10.53 (m, 1H).

MS ESI/APCI Dual posi: 452 [M+H]⁺, 474 [M+H]⁺.

MS ESI/APCI Dual nega: 450 [M−H]⁻.

(2) Synthesis of the titled compound

The compound (560 mg) obtained in step (1) above was used and treated by the same techniques as in Example 1-2(2) and Example 1-3(3) to give the titled compound as a colorless solid (254 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.36-2.55 (m, 5H) 3.21-3.34 (m, 2H) 3.50 (d, J=4.5 Hz, 2H) 4.60 (s, 2H) 7.26-7.45 (m, 3H) 7.59-7.71 (m, 2H) 7.89-7.99 (m, 1H) 8.73 (d, J=2.0 Hz, 1H) 10.01-10.22 (m, 1H).

MS ESI/APCI Dual posi: 396 [M+H]⁺.

MS ESI/APCI Dual nega: 394[M−H]⁻.

Example 2-5 N-({4-Hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine sodium salt

(1) Synthesis of 2-methyl-2-propanyl N-({4-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate

A mixture of the compound (2.00 g) obtained in Example 2-1(1), 5-methylpyridine-2-boronic acid N-phenyldiethanolamine ester (2.32 g), potassium carbonate (1.14 g), copper(I) iodide (313 mg), tri(2-methylphenyl)phosphine (250 mg), palladium(II) acetate (46 mg) and tetrahydrofuran (28.8 mL) was stirred at 95° C. for 4 hours. After cooling the reaction mixture to room temperature, ethyl acetate was added and the precipitate was removed by passage through Celite (registered trademark). The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=80:20-0:100) to give 2-methyl-2-propanyl N-({4-hydroxy-1-[4-(5-methyl-2-pyridinyl)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate as a colorless amorphous mass (1.00 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.37 (s, 3H) 2.47-2.68 (m, 2H) 3.25-3.40 (m, 2H) 4.00-4.07 (m, 2H) 4.67 (s, 2H) 7.31-7.42 (m, 2H) 7.52-7.66 (m, 2H) 7.87-7.99 (m, 2H) 8.45-8.59 (m, 1H) 10.14-10.53 (m, 1H).

MS ESI/APCI Dual posi: 452 [M+H]⁺.

(2) Synthesis of the Titled Compound

The compound (1.00 g) obtained in step (1) above was used and treated by the same techniques as in Example 1-2(2) and Example 1-3(3) to give the titled compound as a colorless solid (505 mg).

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.29 (s, 3H) 2.43-2.59 (m, 2H) 3.22-3.56 (m, 4H) 4.58 (s, 2H) 7.28-7.39 (m, 2H) 7.60-7.69 (m, 1H) 7.75-7.85 (m, 1H) 7.94-8.04 (m, 2H) 8.45 (s, 1H) 9.87-10.31 (m, 1H).

MS ESI/APCI Dual posi: 396 [M+H]⁺.

In the following Examples 2-6 to 2-54, the compound obtained in Reference Examples A-4, A-5, A-303, A-304 or A-305 was used as the starting material which, together with a commercial grade of the corresponding boronic acids or boronic acid esters, was treated by the methods described in Example 2-1(1) and (2) or in step (1) of each of Examples 2-2 to 2-5 or modifications thereof, and the compounds thus obtained were further treated by the method described in Example 1-1(4), 1-2(2) or 1-3(3) or modifications thereof to synthesize the intended compounds. The structures of the synthesized compounds and their NMR and MS data are shown in Tables 22-1 to 22-8. The numerals cited in the column “Example” of each table indicate which of the above-noted Examples 2-1 to 2-5 was repeated or modified to synthesize the compound of interest.

TABLE 22-1 Compound Salt No. Structure Analytical Data information Example Example 2-6

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.54-2.77 (m, 2 H) 3.38 (t, J = 7.1 Hz, 2 H) 3.86 (s, 3 H) 4.03 (d, J = 5.6 Hz, 2 H) 4.56 (s, 2 H) 7.27 (d, J = 8.1 Hz, 2 H) 7.53 (d, J = 8.1 Hz, 2 H) 7.83 (s, 1 H) 8.11 (s, 1 H) 10.07 (br. s., 1 H). MS ESI/APCI Dual posi: 385[M + H]⁺, 407[M + Na]⁺. MS ESI/APCI Dual nega: 383[M − H]⁻. 2-1 Example 2-7

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.65-2.76 (m, 2 H) 3.35- 3.53 (m, 2 H) 3.98-4.10 (m, 2 H) 4.60-4.75 (m, 2 H) 7.40- 7.56 (m, 2 H) 7.76-7.87 (m, 2 H) 7.89-7.97 (m, 1 H) 8.58-8.69 (m, 1 H) 8.75-8.83 (m, 1 H) 9.08-9.18 (m, 1 H) 9.94-10.31 (m, 1 H). MS ESI/APCI Dual posi: 382[M + H]⁺. MS ESI/APCI Dual nega: 380[M − H]⁻. HCl 2-1 Example 2-8

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54-2.69 (m, 2 H) 3.37 (t, J = 7.1 Hz, 2 H) 4.16-4.24 (m, 2 H) 4.59- 4.68 (m, 2 H) 7.29-7.37 (m, 2 H) 7.41-7.50 (m, 2 H) 8.52- 8.57 (m, 1 H) 8.65-8.70 (m, 1 H) 10.15-10.47 (m, 1 H). MS ESI/APCI Dual posi: 372[M + H]⁺, 394[M + Na]⁺. MS ESI/APCI Dual nega: 370[M − H]⁻. 2-1 Example 2-9

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.20-1.29 (m, 6 H) 2.47- 2.73 (m, 2 H) 2.90-3.01 (m, 1 H) 3.37-3.47 (m, 2 H) 4.00- 4.09 (m, 2 H) 4.57-4.69 (m, 2 H) 7.19-7.27 (m, 1 H) 7.31-7.51 (m, 5 H) 7.58-7.67 (m, 2 H) 10.02-10.27 (m, 1 H) 12.79-12.90 (m, 1 H). MS ESI/APCI Dual posi: 423[M + H]⁺, 445[M + Na]⁺. MS ESI/APCI Dual nega: 421[M − H]⁻. 2-1 Example 2-10

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.65-2.74 (m, 2 H) 3.39- 3.49 (m, 2 H) 4.00-4.10 (m, 2 H) 4.58-4.71 (m, 2 H) 7.35- 7.43 (m, 3 H) 7.46-7.51 (m, 2 H) 7.68-7.74 (m, 4 H) 7.76 (s, 4 H) 9.98-10.33 (m, 1 H). MS ESI/APCI Dual posi: 457[M + H]⁺, 47

[M + Na]⁺. MS ESI/APCI Dual nega: 455[M − H]⁻. 2-1 Example 2-11

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54-2.69 (m, 2 H) 3.33-3.44 (m, 2 H) 4.15-4.23 (m, 2 H) 4.61-4.69 (m, 2 H) 7.29-7.44 (m, 4 H) 7.45-7.57 (m, 4 H) 10.15-10.46 (m, 1 H). MS ESI/APCI Dual posi: 415[M + H]⁺, 437[M + Na]⁺. MS ESI/APCI Dual nega: 413[M − H]⁻. 2-1 Example 2-12

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.46-2.76 (m, 2 H) 3.30- 3.51 (m, 2 H) 3.74-3.83 (m, 3 H) 3.99-4.08 (m, 2 H) 4.53- 4.69 (m, 2 H) 6.96-7.07 (m, 2 H) 7.29-7.40 (m, 2 H) 7.52-7.66 (m, 4 H) 10.00-10.29 (m, 1 H) 12.62-13.06 (m, 1 H). MS ESI/APCI Dual posi: 411[M + H]⁺, 433[M + Na]⁺. MS ESI/APCI Dual nega: 409[M − H]⁻. 2-1

indicates data missing or illegible when filed

TABLE 22-2 Compound Salt No. Structure Analytical Data information Example Example 2-13

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.47-2.74 (m, 2 H) 3.38- 3.45 (m, 2 H) 3.90 (s, 3 H) 4.01-4.06 (m, 2 H) 4.59-4.65 (m, 2 H) 6.90-6.94 (m, 1 H) 7.36-7.40 (m, 2 H) 7.62- 7.66 (m, 2 H) 7.99-8.03 (m, 1 H) 8.46-8.49 (m, 1 H) 9.95- 10.29 (m, 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺, 434[M + Na]⁺. MS ESI/APCI Dual nega: 410[M − H]⁻. HCl 2-1 Example 2-14

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.47-2.76 (m, 2 H) 3.37- 3.75 (m, 2 H) 3.98-4.09 (m, 2 H) 4.58-4.72 (m, 2 H) 7.43 (d, J = 8.2 Hz, 2 H) 7.74 (d, J = 8.2 Hz, 2 H) 7.83-7.98 (m, 4 H) 9.96-10.29 (m, 1 H). MS ESI posi: 406[M + H]⁺. MS ESI nega: 404[M − H]⁻. 2-1 Example 2-15

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.44-2.76 (m, 8 H) 3.34- 3.49 (m, 2 H) 3.95-4.09 (m, 2 H) 4.58-4.72 (m, 2 H) 7.36- 7.48 (m, 2 H) 7.68-7.85 (m, 4 H) 7.87-7.97 (m, 2 H) 9.98-10.27 (m, 1 H). MS ESI posi: 488[M + H]⁺. MS ESI nega: 486[M − H]⁻. 2-1 Example 2-16

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.59 (s, 3 H) 2.47-2.77 (m, 2 H) 3.31-3.77 (m, 2 H) 3.93-4.11 (m, 2 H) 4.56-4.73 (m, 2 H) 7.35-7.49 (m, 2 H) 7.65-7.88 (m, 4 H) 7.96- 8.09 (m, 2 H) 9.98-10.33 (m, 1 H). MS ESI posi: 423[M + H]⁺. MS ESI nega: 421[M − H]⁻. 2-1 Example 2-17

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.62-2.79 (m, 2 H) 3.38- 3.50 (m, 2 H) 3.85 (s, 3 H) 3.98-4.08 (m, 2 H) 4.56-4.72 (m, 2 H) 6.39 (d, J = 1.9 Hz, 1 H) 7.35-7.57 (m, 5 H) 9.93- 10.32 (m, 1 H). MS ESI posi: 385[M + H]⁺. 2-1 Example 2-18

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.60-2.76 (m, 2 H) 3.31- 3.48 (m, 2 H) 3.95-4.10 (m, 2 H) 4.53-4.69 (m, 2 H) 7.23- 7.40 (m, 2 H) 7.49-7.58 (m, 1 H) 7.59-7.75 (m, 3 H) 7.80-7.90 (m, 1 H) 9.99-10.31 (m, 1 H). MS ESI posi: 387[M + H]⁺. MS ESI nega: 385[M − H]⁻. 2-1 Example 2-19

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.65-2.79 (m, 2 H) 3.40- 3.76 (m, 2 H) 3.97-4.10 (m, 2 H) 4.61-4.77 (m, 2 H) 7.46- 7.58 (m, 2 H) 7.91-8.04 (m, 2 H) 8.21-8.32 (m, 2 H) 8.83-8.94 (m, 2 H) 9.96-10.31 (m, 1 H). MS ESI posi: 382[M + H]⁺. MS ESI nega: 380[M − H]⁻. HCl 2-1

TABLE 22-3 Compound Salt No. Structure Analytical Data information Example Example 2-20

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.37 (s, 3 H) 2.57-2.78 (m, 5 H) 3.36-3.52 (m, 2 H) 3.96-4.09 (m, 2 H) 4.55-4.71 (m, 2 H) 7.30-7.49 (m, 4 H) 9.95-10.11 (m, 1 H). MS ESI posi: 416[M + H]⁺. MS ESI nega: 414[M − H]⁻. 2-1 Example 2-21

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.45-2.77 (m, 2 H) 3.34- 3.50 (m, 2 H) 3.94-4.11 (m, 2 H) 4.58-4.77 (m, 2 H) 7.38- 7.54 (m, 2 H) 7.73-7.87 (m, 2 H) 7.94-8.04 (m, 1 H) 8.28- 8.42 (m, 1 H) 9.04-9.13 (m, 1 H) 9.94-10.32 (m, 1 H). MS ESI posi: 450[M + H]⁺. MS ESI nega: 448[M − H]⁻. 2-1 Example 2-22

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.46-2.75 (m, 2 H) 3.36- 3.48 (m, 2 H) 3.96-4.09 (m, 2 H) 4.57-4.71 (m, 2 H) 7.32- 7.54 (m, 4 H) 7.58-7.74 (m, 4 H) 9.97-10.28 (m, 1 H). MS ESI/APCI Dual posi: 415[M + H]⁺. MS ESI/APCI Dual nega: 413[M − H]⁻. 2-1 Example 2-23

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.49-2.76 (m, 2 H) 3.33- 3.51 (m, 2 H) 3.98-4.08 (m, 2 H) 4.58-4.69 (m, 2 H) 7.35- 7.44 (m, 2 H) 7.64-7.75 (m, 4 H) 7.90-7.96 (m, 1 H) 9.99-10.27 (m, 1 H). MS ESI/APCI Dual posi: 449[M + H]⁺. MS ESI/APCI Dual nega: 447[M − H]⁻. 2-1 Example 2-24

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.51-2.76 (m, 2 H) 3.37- 3.51 (m, 2 H) 3.98-4.09 (m, 2 H) 4.59-4.74 (m, 2 H) 7.38- 7.49 (m, 2 H) 7.67-7.95 (m, 6 H) 10.00-10.28 (m, 1 H). MS ESI/APCI Dual posi: 449[M + H]⁺. MS ESI/APCI Dual nega: 447[M − H]⁻. 2-1 Example 2-25

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.37 (s, 3 H) 2.48-2.75 (m, 2 H) 3.34-3.48 (m, 2 H) 3.97-4.10 (m, 2 H) 4.53-4.73 (m, 2 H) 7.10-7.23 (m, 1 H) 7.28-7.50 (m, 5 H) 7.53- 7.71 (m, 2 H) 9.95-10.30 (m, 1 H). MS ESI/APCI Dual posi: 395[M + H]⁺. 2-1 Example 2-26

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.48-2.76 (m, 2 H) 3.33- 3.47 (m, 2 H) 3.82 (s, 3 H) 3.97-4.10 (m, 2 H) 4.56-4.69 (m, 2 H) 6.89-6.97 (m, 1 H) 7.13-7.25 (m, 2 H) 7.31-7.43 (m, 3 H) 7.58-7.70 (m, 2 H) 9.98-10.29 (m, 1 H). MS ESI/APCI Dual posi: 411[M + H]⁺. MS ESI/APCI Dual nega: 409[M − H]⁻. 2-1

TABLE 22-4 Compound Salt No. Structure Analytical Data information Example Example 2-27

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.65-2.76 (m, 2 H) 3.36- 3.53 (m, 2 H) 3.98-4.09 (m, 2 H) 4.61-4.75 (m, 2 H) 7.43- 7.53 (m, 2 H) 7.67-7.76 (m, 1 H) 7.80-7.91 (m, 2 H) 8.11-8.25 (m, 2 H) 8.37-8.43 (m, 1 H) 8.60-8.70 (m, 1 H) 8.99-9.07 (m, 1 H) 10.01-10.29 (m, 1 H) MS ESI/APCI Dual posi: 432[M + H]⁺. TFA 2-1 Example 2-28

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.62-2.75 (m, 2 H) 3.34- 3.52 (m, 2 H) 3.94-4.13 (m, 2 H) 4.53-4.73 (m, 2 H) 7.19- 7.46 (m, 4 H) 7.54-7.77 (m, 4 H) 9.99-10.30 (m, 1 H) 12.69-13.01 (m, 1 H). MS ESI/APCI Dual posi: 399[M + H]⁺, 421[M + Na]⁺. 2-1 Example 2-29

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.56-2.72 (m, 2 H) 3.35-3.47 (m, 2 H) 4.15-4.25 (m, 2 H) 4.60-4.68 (m, 2 H) 7.04-7.17 (m, 4 H) 7.32-7.41 (m, 1 H) 7.45-7.54 (m, 2 H) 10.08-10.50 (m, 1 H). MS ESI/APCI Dual posi: 439[M + Na]⁺. MS ESI/APCI Dual nega: 415[M − H]⁻. 2-1 Example 2-30

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.68 (t, J = 7.1 Hz, 2 H) 3.32-3.47 (m, 2 H) 3.91-4.14 (m, 2 H) 4.52-4.70 (m, 2 H) 6.84 (d, J = 8.4 Hz, 2 H) 7.32 (d, J = 7.9 Hz, 2 H) 7.39-7.64 (m, 4 H) 9.53 (br. s., 1 H) 9.93-10.33 (m, 1 H). MS ESI posi: 397[M + H]⁺, 419[M + Na]⁺. 2-1

TABLE 22-5 Compound Salt No. Structure Analytical Data information Example Example 2-31

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.56-2.79 (m, 2 H) 3.07- 3.29 (m, 3 H) 3.36-3.52 (m, 2 H) 3.81-4.21 (m, 2 H) 4.57- 4.73 (m, 2 H) 7.37-7.53 (m, 2 H) 7.65-7.82 (m, 2 H) 7.89- 8.05 (m, 4 H) 9.94-10.33 (m, 1 H). MS ESI/APCI Dual posi: 459[M + H]⁺. MS ESI/APCI Dual nega: 457[M − H]⁻. 2-1 Example 2-32

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.63-2.76 (m, 2 H) 2.89- 3.05 (m, 6 H) 3.36-3.48 (m, 2 H) 3.97-4.08 (m, 2 H) 4.56- 4.71 (m, 2 H) 7.36-7.42 (m, 2 H) 7.49 (d, J = 8.1 Hz, 2 H) 7.70 (t, J = 8.1 Hz, 4 H) 9.96-10.31 (m, 1 H). MS ESI/APCI Dual posi: 452[M + H]⁺. MS ESI/APCI Dual nega: 450[M − H]⁻. 2-1 Example 2-33

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.00-1.26 (m, 1 H) 1.50-2.08 (m, 9 H) 4.20 (d, J = 5.8 Hz, 2 H) 4.58 (s, 2 H) 7.27-7.57 (m, 8 H) 8.17-8.33 (m, 1 H). MS ESI/APCI Dual posi: 469[M + H]⁺. MS ESI/APCI Dual nega: 467[M − H]⁻. 2-2 Example 2-34

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.70 (t, J = 7.2 Hz, 2 H) 3.36-3.55 (m, 2 H) 3.96-4.09 (m, 2 H) 4.54-4.71 (m, 2 H) 7.41 (d, J = 8.4 Hz, 2 H) 7.64-7.86 (m, 4 H) 8.01 (d, J = 8.4 Hz, 2 H) 9.94-10.32 (m, 1 H) 12.91 (br. s., 2 H). MS ESI/APCI Dual posi: 425[M + H]⁺. MS ESI/APCI Dual nega: 423[M − H]⁻. 2-2 Example 2-35

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.55-2.73 (m, 2 H) 3.39- 3.49 (m, 2 H) 3.75-3.91 (m, 5 H) 4.61 (s, 2 H) 6.96-7.10 (m, 2 H) 7.70-7.79 (m, 1 H) 7.82-7.91 (m, 1 H) 7.98-8.08 (m, 2 H) 8.52-8.60 (m, 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺. MS ESI/APCI Dual nega: 410[M − H]⁻. Na 2-3 Example 2-36

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.54-2.71 (m, 2 H) 3.38- 3.48 (m, 2 H) 3.58-3.70 (m, 2 H) 4.64 (s, 2 H) 7.42-7.52 (m, 2 H) 7.77-7.85 (m, 1 H) 7.94-8.03 (m, 1 H) 8.15-8.25 (m, 2 H) 8.59-8.65 (m, 1 H). MS ESI/APCI Dual posi: 466[M + H]⁺. MS ESI/APCI Dual nega: 464[M − H]⁻. Na 2-3 Example 2-37

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.38-2.60 (m, 2 H) 3.44 (d, J = 4.2 Hz, 2 H) 4.61 (s, 2 H) 7.23-7.40 (m, 2 H) 7.74- 7.83 (m, 1 H) 7.89-7.97 (m, 1 H) 8.07-8.18 (m, 2 H) 8.56- 8.63 (m, 1 H). MS ESI/APCI Dual posi: 400[M + H]⁺. MS ESI/APCI Dual nega: 398[M − H]⁻. Na 2-3

TABLE 22-6 Compound Salt No. Structure Analytical Data information Example Example 2-38

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.41-2.61 (m, 2 H) 3.40- 3.50 (m, 2 H) 3.80 (s, 3 H) 4.67 (s, 2 H) 6.98-7.11 (m, 2 H) 7.28-7.38 (m, 1 H) 7.59-7.72 (m, 2 H) 7.94-8.03 (m, 1 H) 8.74-8.81 (m, 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺. MS ESI/APCI Dual nega: 410[M − H]⁻. Na 2-3 Example 2-39

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.56-2.77 (m, 2 H) 3.45- 3.71 (m, 4 H) 4.71 (s, 2 H) 7.34-7.55 (m, 3 H) 7.79-7.92 (m, 2 H) 8.02-8.12 (m, 1 H) 8.81-8.89 (m, 1 H). Na 2-3 Example 2-40

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.48-2.76 (m, 2 H) 3.37- 3.61 (m, 4 H) 4.72 (s, 2 H) 7.38-7.47 (m, 1 H) 7.79-7.90 (m, 2 H) 7.91-8.03 (m, 2 H) 8.08-8.18 (m, 1 H) 8.86-8.94 (m, 1 H). Na 2-3 Example 2-41

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.48-2.65 (m, 2 H) 3.28- 3.52 (m, 4 H) 3.89 (s, 3 H) 4.62 (s, 2 H) 7.06-7.12 (m, 1 H) 7.26-7.34 (m, 1 H) 7.37-7.45 (m, 2 H) 7.70-7.81 (m, 2 H) 8.17-8.25 (m, 1 H). Na 2-3 Example 2-42

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.41-2.53 (m, 2 H) 3.22- 3.40 (m, 7 H) 4.51 (s, 2 H) 7.24-7.29 (m, 2 H) 7.31-7.36 (m, 2 H) 7.54 (s, 1 H) 9.85-9.99 (m, 1 H). MS ESI/APCI Dual posi: 418[M + H]⁺. Na 2-2 Example 2-43

¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.45-2.56 (m, 2 H) 3.21- 3.47 (m, 4 H) 4.52 (s, 2 H) 7.20-7.26 (m, 2 H) 7.28-7.39 (m, 3 H) 8.54 (s, 1 H) 9.81-10.16 (m, 1 H). MS ESI/APCI Dual posi: 404[M + H]⁺. Na 2-2 Example 2-44

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.28-2.42 (m, 5 H) 3.21- 3.54 (m, 4 H) 4.66 (s, 2 H) 7.25-7.36 (m, 3 H) 7.55-7.63 (m, 2 H) 7.93-8.04 (m, 1 H) 8.73-8.80 (m, 1 H) 10.08- 10.20 (m, 1 H). MS ESI/APCI Dual posi: 396[M + H]⁺. Na 2-3

TABLE 22-7 Compound Salt No. Structure Analytical Data information Example Example 2-45

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.36 (s, 3 H) 2.44-2.62 (m, 2 H) 3.26-3.56 (m, 4 H) 4.61 (s, 2 H) 7.24-7.35 (m, 2 H) 7.70-7.80 (m, 1 H) 7.86-8.03 (m, 3 H) 8.55-8.61 (m, 1 H) 9.99-10.16 (m, 1 H). MS ESI/APCI Dual posi: 396[M + H]⁺. Na 2-3 Example 2-46

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.45-2.61 (m, 2 H) 3.25-3.59 (m, 4 H) 4.62 (s, 2 H) 7.48-7.59 (m, 2 H) 7.74- 7.84 (m, 1 H) 7.90-8.01 (m, 1 H) 8.05-8.16 (m, 2 H) 8.61 (s, 1 H) 9.99-10.17 (m, 1 H). MS ESI/APCI Dual posi: 416[M + H]⁺. Na 2-3 Example 2-47

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.40-2.58 (m, 5 H) 3.21-3.58 (m, 4 H) 4.56 (s, 2 H) 6.77-6.84 (m, 1 H) 7.22- 7.34 (m, 3 H) 7.49-7.59 (m, 2 H) 9.98-10.21 (m, 1 H). MS ESI/APCI Dual posi: 401[M + H]⁺. Na 2-2 Example 2-48

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.67-0.78 (m, 2 H) 0.94- 1.05 (m, 2 H) 1.88-2.04 (m, 1 H) 2.47-2.61 (m, 2 H) 3.37 (t, J = 7.0 Hz, 2 H) 3.51-3.59 (m, 2 H) 4.60 (s, 2 H) 7.13-7.22 (m, 2 H) 7.70-7.79 (m, 1 H) 7.84-8.00 (m, 3 H) 8.54-8.61 (m, 1 H) 10.06-10.18 (m, 1 H). MS ESI/APCI Dual posi: 422[M + H]⁺. Na 2-3 Example 2-49

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.66-0.75 (m, 2 H) 0.91- 1.03 (m, 2 H) 1.88-2.03 (m, 1 H) 2.48-2.62 (m, 2 H) 3.34 (t, J = 7.1 Hz, 2 H) 3.60 (d, J = 4.5 Hz, 2 H) 4.60 (s, 2 H) 7.08- 7.20 (m, 2 H) 7.30-7.39 (m, 2 H) 7.48-7.65 (m, 4 H) 10.06- 10.21 (m, 1 H). MS ESI/APCI Dual posi: 421[M + H]⁺. Na 2-3 Example 2-50

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.67-0.78 (m, 2 H) 0.88- 1.07 (m, 2 H) 1.90-2.05 (m, 1 H) 2.49-2.64 (m, 2 H) 3.38- 3.56 (m, 4 H) 4.68 (s, 2 H) 7.13-7.26 (m, 2 H) 7.29-7.39 (m, 1 H) 7.53-7.64 (m, 2 H) 7.92-8.06 (m, 1 H) 8.72-8.84 (m, 1 H) 9.96-10.16 (m, 1 H). MS ESI/APCI Dual posi: 422[M + H]⁺. Na 2-3 Example 2-51

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.40-2.54 (m, 2 H) 3.34 (t, J = 6.9 Hz, 2 H) 3.53 (d, J = 4.5 Hz, 2 H) 3.83 (s, 3 H) 4.61 (s, 2 H) 6.93-7.06 (m, 1 H) 7.32-7.46 (m, 1 H) 7.58-7.68 (m, 2 H) 7.72-7.82 (m, 1 H) 7.87-7.99 (m, 1 H) 8.55-8.67 (m, 1 H) 10.05-10.21 (m, 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺. Na 2-3

TABLE 22-8 Compound Salt No. Structure Analytical Data information Example Example 2-52

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.53-2.66 (m, 2 H) 3.41 (t, J = 7.1 Hz, 2 H) 3.62 (d, J = 4.7 Hz, 2 H) 3.82 (s, 3 H) 4.62 (s, 2 H) 7.01-7.19 (m, 2 H) 7.32-7.48 (m, 1 H) 7.66-7.85 (m, 3 H) 8.54-8.66 (m, 1 H) 10.02-10.19 (m, 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺. Na 2-3 Example 2-53

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.47-2.61 (m, 2 H) 3.34 (t, J = 7.0 Hz, 2 H) 3.57 (d, J = 4.4 Hz, 2 H) 3.90 (s, 3 H) 4.62 (s, 2 H) 7.34-7.47 (m, 2 H) 7.57-7.65 (m, 1 H) 7.69-7.77 (m, 2 H) 8.25-8.31 (m, 1 H) 8.44-8.50 (m, 1 H) 10.07-10.22 (m, 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺. Na 2-2 Example 2-54

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.45-2.61 (m, 2 H) 3.28- 3.41 (m, 2 H) 3.49-3.60 (m, 2 H) 3.85 (s, 3 H) 4.61 (s, 2 H) 7.11-7.23 (m, 1 H) 7.27-7.41 (m, 2 H) 7.43-7.55 (m, 2 H) 8.30- 8.52 (m, 2 H) 10.06-10.23 (m, 1 H). MS ESI/APCI Dual posi: 412[M + H]⁺. Na 2-2

Example 2-55 N-({4-Hydroxy-2-oxo-1-[(4′-sulfamoyl-4-biphenylyl)methyl]-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine

(1) Synthesis of N-{[4-hydroxy-(4-iodobenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine

To the compound (5.00 g) obtained in Example 2-1(1), a solution (50 mL) of 4 mol/L, hydrogen chloride in 1,4-dioxane was added and the mixture was stirred at 70° C. for three hours. The reaction mixture was cooled with ice and the resulting precipitate was recovered by filtration to give N-{[4-hydroxy-1-(4-iodobenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine as a colorless solid (3.37 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.65 (br. s., 2H) 3.37 (t, J=7.1 Hz, 2H) 4.02 (d, J=5.8 Hz, 2H) 4.53 (s, 2H) 7.11 (d, J=8.4 Hz, 2H) 7.62-7.81 (m, 2H) 10.03 (br. s., 1H).

MS ESI/APCI Dual posi: 453 [M+Na]⁺.

MS ESI/APCI Dual nega: 429 [M−H]⁻.

(2) Synthesis of the Titled Compound

The compound (100 mg) obtained in step (1) above was used and treated by the same technique as in Example 2-2(1) to give the titled compound as a pale yellow solid (45.9 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.65-2.75 (m, 2H) 3.37-3.49 (m, 2H) 3.96-4.11 (m, 2H) 4.59-4.71 (m, 2H) 7.33-7.44 (m, 4H) 7.68-7.76 (m, 2H) 7.81-7.93 (m, 4H) 9.88-10.33 (m, 1H) 12.85 (br. s., 1H).

MS ESI/APCI Dual posi: 460 [M+H]⁺.

MS ESI/APCI Dual nega: 458 [M−H]⁻.

The compounds of the following Examples 2-56 to 2-61 were synthesized from commercial grades of the corresponding boronic acid analogs by the method described in Example 2-55 or modifications thereof. The structures of the synthesized compounds and their NMR and MS data are shown in Table 22-9.

TABLE 22-9 Compound Salt No. Structure Analytical Data information Example 2-56

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.55-2.69 (m, 2 H) 3.39 (t, J = 7.0 Hz, 2 H) 3.57 (d, J = 4.7 Hz, 2 H) 4.65 (s, 2 H) 7.47 (d, J = 8.2 Hz, 2 H) 7.82 (d, J = 8.2 Hz, 2 H) 8.11 (d, J = 8.4 Hz, 1 H) 8.42 (dd, J = 8.4, 2.2 Hz, 1 H) 9.10 (d, J = 1.6 Hz, 1 H) 10.04 (br. s., 1 H). MS ESI/APCI Dual posi: 460[M + H]⁺. MS ESI/APCI Dual nega: 458[M − H]⁻. Na Example 2-57

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.60 (br. s., 2 H) 2.82 (q, J = 6.3 Hz, 2 H) 3.28-3.47 (m, 6 H) 3.64 (d, J = 4.7 Hz, 2 H) 4.63 (s, 2 H) 7.42 (d, J = 8.2 Hz, 2 H) 7.64-7.79 (m, 3 H) 7.80- 7.96 (m, 4 H) 10.08 (br. s., 1 H). MS ESI/APCI Dual posi: 504[M + H]⁺. MS ESI/APCI Dual nega: 502[M − H]⁻. Na Example 2-58

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.60-2.78 (m, 2 H) 3.43 (t, J = 7.0 Hz, 2 H) 4.03 (d, J = 5.6 Hz, 2 H) 4.66 (s, 2 H) 7.46 (d, J = 8.2 Hz, 2 H) 7.81 (d, J = 8.2 Hz, 2 H) 8.13 (dd, J = 8.2, 0.7 Hz, 1 H) 8.29 (dd, J = 8.2, 2.3 Hz, 1 H) 9.02 (dd, J = 2.3, 0.7 Hz, 1 H) 10.05 (br. s., 1 H). MS ESI/APCI Dual posi: 426[M + H]⁺. MS ESI/APCI Dual nega: 424[M − H]⁻. HCl Example 2-59

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.69 (br. s., 2 H) 3.33- 3.47 (m, 2 H) 4.03 (d, J = 5.6 Hz, 2 H) 4.62 (s, 2 H) 7.12 (d, J = 9.9 Hz, 1 H) 7.40 (d, J = 8.2 Hz, 2 H) 7.65 (d, J = 8.2 Hz, 2 H) 8.15-8.40 (m, 4 H) 10.05 (br. s., 1 H). MS ESI/APCI Dual posi: 397[M + H]⁺. HCl Example 2-60

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.58-2.75 (m, 2 H) 3.33- 3.45 (m, 2 H) 4.03 (d, J = 5.8 Hz, 2 H) 4.59 (s, 2 H) 6.58 (d, J = 9.5 Hz, 1 H) 7.34 (d, J = 8.2 Hz, 2 H) 7.56 (d, J = 8.2 Hz, 2 H) 7.81 (d, J = 2.6 Hz, 1 H) 7.94 (dd, J = 9.5, 2.6 Hz, 1 H) 10.07 (br. s., 1 H). MS ESI/APCI Dual posi: 398[M + H]⁺. MS ESI/APCI Dual nega: 396[M − H]⁻. HCl Example 2-61

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.68 (br. s., 2 H) 3.36- 3.47 (m, 2 H) 4.03 (d, J = 5.6 Hz, 2 H) 4.62 (s, 2 H) 7.41 (d, J = 8.4 Hz, 2 H) 7.70 (d, J = 8.4 Hz, 2 H) 8.93 (s, 2 H) 10.05 (br. s., 1 H). MS ESI/APCI Dual posi: 398[M + H]⁺. MS ESI/APCI Dual nega: 396[M − H]⁻. HCl

Example 3-1 N-{[1-(4-Cyclopentylbenzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycine sodium salt

(1) Synthesis of tert-butyl N-[1-(4-cyclopentylbenzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl glycinate

Indium(III) chloride (768 mg) was dried under reduced pressure while it was heated with a thermal gun. After being left to cool to room temperature, the reaction system was internally purged with argon. To the reaction system, dehydrated tetrahydrofuran (20.0 mL) was added and with stirring at −80° C., cyclopentyl magnesium bromide (2.0 mol/L, solution in diethyl ether, 5.23 mL) was added dropwise. After being stirred at that temperature for 30 minutes, the reaction mixture was brought to room temperature and stirred for 45 minutes. The compound (1.50 g) obtained in Example 2-1(1) and bis(tri-tert-butylphosphine)palladium(0) (788 mg) were added and the mixture was stirred at an external temperature of 75° C. for two hours. After standing to cool to room temperature, methanol (5.00 mL) was added and the mixture was stirred for 30 minutes. After concentrating under reduced pressure, chloroform (30.0 mL) was added and the insoluble matter was removed by passage through Celite (registered trademark). The filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC and further purified twice by silica gel column chromatography (chloroform:ethyl acetate=100:0-85:15) to give tert-butyl N-{[1-(4-cyclopentylbenzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycinate as a pale brown oil (600 mg).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 1.51-1.61 (m, 2H) 1.64-1.73 (m, 2H) 1.75-1.84 (m, 2H) 2.01-2.10 (m, 2H) 2.48-2.62 (m, 2H) 2.93-3.03 (m, 1H) 3.28-3.38 (m, 2H) 3.97-4.06 (m, 2H) 4.58 (s, 2H) 7.14-7.24 (m, 4H) 10.19-10.46 (m, 1H).

MS ESI/APCI Dual posi: 451 [M+Na]⁺.

(2) Synthesis of the Titled Compound

The compound (590 mg) obtained in step (1) above was used as a starting material and treated by the same techniques as in Example 1-3(2) and (3) to give the titled compound as an orange solid (118 mg).

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.46-1.55 (m, 2H) 1.58-1.68 (m, 2H) 1.70-1.80 (m, 2H) 1.93-2.03 (m, 2H) 2.48-2.60 (m, 2H) 2.89-2.98 (m, 1H) 3.27-3.34 (m, 2H) 3.62-3.68 (m, 2H) 4.52 (s, 2H) 7.13-7.25 (m, 4H) 10.01-10.22 (m, 1H).

MS ESI posi: 373 [M+H]⁺.

MS ESI nega: 371[M−H]⁻.

Example 3-2

N-{[1-(4-Cyclopropylbenzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycine sodium salt

Instead of cyclopentyl magnesium bromide (2.0 mol/L, solution in diethyl ether), cyclopropyl magnesium bromide (about 0.7 mol/L, solution in tetrahydrofuran) was used and treated by the same technique as in Example 3-1 to give the titled compound as a pale gray solid (527 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.60-0.67 (m, 2H) 0.88-0.96 (m, 2H) 1.81-1.95 (m, 1H) 2.47-2.54 (m, 2H) 3.20-3.30 (m, 2H) 3.47-3.54 (m, 2H) 4.50 (s, 2H) 6.97-7.08 (m, 2H) 7.10-7.19 (m, 2H) 10.08 (br. s., 1H).

MS ESI posi: 345 [M+H]⁺, 367 [M+Na]⁺.

Example 4-1 N-{[1-(2,4-Dimethoxybenzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycine

(1) Synthesis of ethyl N-(2,4-dimethoxybenzyl)-N-(3-ethoxy-3-oxopropanoyl)-β-alaninate

Instead of the compound obtained in Reference Example A-1, the compound obtained in Reference Example A-6 (8.05 g) was used as a starting material and treated by the same technique as in Example 1-1(1) to give a mixture (13.0 g) containing ethyl N-(2,4-dimethoxybenzyl)-N-(3-ethoxy-3-oxo-propanoyl)-β-alaninate.

MS ESI/APCI Dual posi: 382 [M+H]⁺, 404 [M+Na]⁺.

(2) Synthesis of ethyl 1-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridin-3-carboxylate

To a solution in ethanol (160 mL) of the mixture (13.0 g) obtained in step (1) above, sodium ethoxide (about 20%, solution in ethanol, 20.8 mL) was added and the resulting mixture was stirred at an external temperature of 85° C. for two hours. After cooling to room temperature, ethyl acetate and 2 mol/L hydrochloric acid were added. Extraction was conducted with ethyl acetate and the combined organic layers were washed with saturated brine. After drying over anhydrous magnesium sulfate and removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-5:95) to give ethyl 1-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridin-3-carboxylate as a brown oil (8.20 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.40 (t, J=7.1 Hz, 3H) 2.55 (t, J=6.6 Hz, 2H) 3.33-3.44 (m, 2H) 3.75-3.85 (m, 6H) 4.38 (q, J=7.1 Hz, 2H) 4.57 (s, 2H) 6.37-6.50 (m, 2H) 7.20-7.26 (m, 1H).

MS ESI/APCI Dual posi: 336 [M+H]⁺.

MS ESI/APCI Dual nega: 334[M−H]⁻.

(3) Synthesis of 2-(trimethylsilyl)ethyl N-{[1-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycinate

To a solution in 1,2-dimethoxyethane (4.60 mL) of the compound (311 mg) obtained in step (2) above, the compound (195 mg) obtained in Reference Example E-1 was added and the mixture was refluxed for two hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. Purification by silica gel column chromatography (n-hexane:ethyl acetate=95:5-65:35) gave 2-(trimethylsilyl)ethyl N-{[1-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycinate as a pale yellow oil (283 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm −0.03-0.01 (m, 9H) 0.97-1.07 (m, 2H) 2.48-2.62 (m, 2H) 3.33-3.43 (m, 2H) 3.76-3.84 (m, 6H) 4.03-4.13 (m, 2H) 4.22-4.29 (m, 2H) 4.52-4.59 (m, 2H) 6.41-6.50 (m, 2H) 7.11-7.23 (m, 1H).

(4) Synthesis of the Titled Compound

To a solution in tetrahydrofuran (3.00 mL) of the compound (283 mg) obtained in step (3) above, tetrabutylammonium fluoride hydrate (1 mol/L, solution in tetrahydrofuran, 0.609 mL) was added and the mixture was stirred at room temperature for 12 hours. More tetrabutylammonium fluoride hydrate (1 mol/L, solution in tetrahydrofuran, 0.609 mL) was added and the mixture was stirred at room temperature for 24.5 hours. The solvent was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-80:20). To a solution in ethanol of the resulting residue, water was added and the mixture was stirred for 60 hours. After cooling to 0° C., the precipitate was recovered by filtration to give the titled compound as a colorless solid (163 mg).

¹H NMR (200 MHz, DMSO-d₆) δ ppm 2.36-2.74 (m, 2H) 3.22-3.43 (m, 2H) 3.75 (s, 3H) 3.79 (s, 3H) 3.99 (d, J=5.7 Hz, 2H) 4.37-4.52 (m, 2H) 6.35-6.63 (m, 2H) 7.07 (d, J=7.5 Hz, 1H) 9.91-10.22 (m, 1H).

MS ESI/APCI Dual posi: 365 [M+H]⁺, 387 [M+Na]⁺.

MS ESI/APCI Dual nega: 363 [M−H]⁻.

Example 4-2 N-({4-Hydroxy-2-oxo-1-[4-(prop-2-en-1-yloxy)benzyl]-1,2,5,6-tetrahydropyridin-3-yl}carbonyl)glycine

Instead of the compound obtained in Reference Example A-6, the compound obtained in Reference Example A-7 (1.34 g) was used as a starting material and treated by the same technique as in Example 4-1 to give the titled compound as a colorless solid (115 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.48-2.69 (m, 2H) 3.24-3.40 (m, 2H) 4.12-4.24 (m, 2H) 4.47-4.61 (m, 4H) 5.24-5.34 (m, 1H) 5.35-5.47 (m, 1H) 6.05 (ddt, J=17.3, 10.5, 5.2 Hz, 1H) 6.84-6.93 (m, 2H) 7.14-7.23 (m, 2H) 10.06-10.49 (m, 1H).

MS ESI/APCI Dual posi: 361 [M+H]⁺, 383 [M+Na]⁺.

MS ESI/APCI Dual nega: 359 [M−H]⁻.

Example 4-3 N-{[4-Hydroxy-1-(4-hydroxybenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine

(1) Synthesis of 2-(trimethylsilyl)ethyl N-({1-[4-(allyloxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate

Instead of the compound obtained in Reference Example A-6, the compound (1.34 g) obtained in Reference Example A-7 was used as a starting material and treated by the same techniques as in Example 4-1(1) to (3) to give 2-(trimethylsilyl)ethyl N-({1-[4-(allyloxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate as a pale yellow oil (1.16 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.05 (s, 9H) 0.97-1.09 (m, 2H) 2.45-2.64 (m, 2H) 3.25-3.37 (m, 2H) 4.05-4.16 (m, 2H) 4.23-4.32 (m, 2H) 4.50-4.56 (m, 4H) 5.24-5.34 (m, 1H) 5.35-5.47 (m, 1H) 6.05 (ddt, J=17.3, 10.6, 5.3, 5.3 Hz, 1H) 6.83-6.93 (m, 2H) 7.14-7.22 (m, 2H) 10.19-10.53 (m, 1H).

MS ESI/APCI Dual posi: 461[M+H]⁺.

MS ESI/APCI Dual nega: 459 [M−H]⁻.

(2) Synthesis of 2-(trimethylsilyl)ethyl N-{[4-hydroxy-1-(4-hydroxybenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycinate

To a solution in tetrahydrofuran (3.8 mL) of the compound (520 mg) obtained in step (1) above, tetrakis(triphenylphosphine)palladium(0) (261 mg) and morpholine (492 μL) were added and the mixture was stirred at room temperature for 22.5 hours. After concentrating under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=85:15-55:45) to give 2-(trimethylsilyl)ethyl N-{[4-hydroxy-1-(4-hydroxybenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycinate as a pale yellow oil (362 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.05 (s, 9H) 0.96-1.12 (m, 2H) 2.46-2.66 (m, 2H) 3.24-3.37 (m, 2H) 4.05-4.16 (m, 2H) 4.22-4.35 (m, 2H) 4.54 (s, 2H) 6.74-6.86 (m, 2H) 7.10-7.19 (m, 2H) 10.16-10.49 (m, 1H).

MS ESI/APCI Dual posi: 421 [M+H]⁺, 443 [M+Na]⁺.

MS ESI/APCI Dual nega: 419 [M−H]⁻, 455 [M+Cl]⁻.

(3) Synthesis of the Titled Compound

The compound (362 mg) obtained in step (2) above was used and treated by the same technique as in 4-1(4) to give the titled compound as a colorless amorphous mass (138 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.38-2.71 (m, 2H) 3.25-3.36 (m, 2H) 3.96-4.09 (m, 2H) 4.39-4.54 (m, 2H) 6.65-6.79 (m, 2H) 7.04-7.15 (m, 2H) 9.25-9.46 (m, 1H) 10.01-10.26 (m, 1H).

MS ESI/APCI Dual posi: 343 [M+Na]⁺.

MS ESI/APCI Dual nega: 319[M−H]⁻.

Example 5-1 and Example 5-2 N-{[(5S)-1-(Biphenyl-4-ylmethyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycine sodium salt Example 5-1 N-{[(5R)-1-(Biphenyl-4-ylmethyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycine sodium salt Example 5-2

The compound (2.00 g) obtained in Example 1-22 was isolated and purified by optical preparative HPLC to give a less polar isomer (956 mg, 99.9% ee) and a more polar isomer (861 mg, 94.1% ee). To a solution of the resulting less polar isomer (956 mg) in acetone, 1 mol/L sodium hydroxide in aqueous solution (2.42 mL) was added. The resulting precipitate was recovered by filtration to give the titled compound of Example 5-1 as a colorless solid (560 mg, 99.9% ee). The aforementioned more polar isomer (861 mg) was likewise treated using 1 mol/L sodium hydroxide in aqueous solution (2.18 mL) to give the titled compound of Example 5-2 as a colorless solid (393 mg, 98.7% ee). The compounds of Examples 5-1 and 5-2 were respectively converted to the compounds described in Reference Examples X-1 and X-2 cited hereinafter and the absolute configuration at position 5 of the 2-oxo-1,2,5,6-tetrahydropyridine ring of each isomer was determined by X-ray crystallography.

N-[(5S)-1-(Biphenyl-4-ylmethyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycine sodium salt Example 5-1

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.8 Hz, 3H) 2.55-2.74 (m, 1H) 2.96-3.12 (m, 1H) 3.37-3.47 (m, 1H) 3.53 (d, J=4.5 Hz, 2H) 4.45-4.73 (m, 2H) 7.29-7.40 (m, 3H) 7.41-7.50 (m, 2H) 7.59-7.70 (m, 4H) 10.18 (br. s., 1H).

MS ESI/APCI Dual posi: 395 [M+H]⁺.

MS ESI/APCI Dual nega: 393 [M−H]⁻.

Optical HPLC retention time: 9.136 min.

N-{[(5R)-1-(Biphenyl-4-ylmethyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-yl]carbonyl}glycine sodium salt Example 5-2

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.03 (d, J=6.8 Hz, 3H) 2.56-2.74 (m, 1H) 2.97-3.13 (m, 1H) 3.37-3.47 (m, 1H) 3.53 (d, J=4.5 Hz, 2H) 4.45-4.73 (m, 2H) 7.29-7.40 (m, 3H) 7.40-7.50 (m, 2H) 7.59-7.72 (m, 4H) 10.18 (br. s., 1H).

MS ESI/APCI Dual posi: 395 [M+H]⁺.

MS ESI/APCI Dual nega: 393 [M−H]⁻.

Optical HPLC retention time: 9.705 min.

Example 6-1

N-{[1-(4-Biphenylylmethyl)-4-hydroxy-2-oxo-1-azaspiro[4.4]non-3-en-3-yl]carbonyl}glycine

(1) Synthesis of methyl 1-{(4-biphenylylmethyl)[3-({2-[(2-methyl-2-propanyl)oxy]-2-oxoethyl}amino)-3-oxopropanoyl]amino}cyclopentanecarboxylate

Instead of monobenzyl malonate and glycine tert-butyl hydrochloride, the compound (300 mg) obtained in Reference Example G-1 and the compound (513 mg) obtained in Reference Example A-306 were respectively used and treated by the same technique as in Reference Example G-1(1) to give methyl 1-{(4-biphenylylmethyl)[3-({2-[(2-methyl-2-propanyl)oxy]-2-oxoethyl}amino)-3-oxopropanoyl]amino}cyclopentanecarboxylate as a colorless solid (478 mg).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9H) 1.60-1.68 (m, 2H) 1.71-1.80 (m, 2H) 1.84-1.92 (m, 2H) 2.44-2.50 (m, 2H) 3.32 (s, 2H) 3.76 (s, 3H) 3.93 (d, J=5.8 Hz, 2H) 4.73 (s, 2H) 7.33-7.47 (m, 5H) 7.56-7.63 (m, 4H) 7.81-7.88 (m, 1H).

MS ESI posi: 531 [M+Na]⁺.

(2) Synthesis of the titled compound

To a solution in ethanol (5.31 mL) of the compound (270 mg) obtained in step (1) above, cesium carbonate (346 mg) was added and the mixture was stirred at room temperature for an hour. The reaction mixture was concentrated under reduced pressure and 1 mol/L hydrochloric acid was added to the resulting residue. Extraction was conducted with ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. To a solution of the resulting concentrate (253 mg) in chloroform (4.88 mL), trifluoroacetic acid (2.44 mL) was added and the mixture was stirred at room temperature for 15 hours. After concentrating under reduced pressure, the residue was recrystallized with a liquid mixture of n-hexane and ethyl acetate and the precipitate was recovered by filtration to give the titled compound as a colorless solid (335 g).

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.67-1.84 (m, 6H) 1.84-1.92 (m, 2H) 3.97-4.02 (m, 2H) 4.58 (s, 2H) 7.33-7.40 (m, 3H) 7.43-7.48 (m, 2H) 7.61-7.67 (m, 4H) 8.34-8.41 (m, 1H).

MS ESI/APCI Dual posi: 421 [M+H]⁺.

MS ESI/APCI Dual nega: 419[M−H]⁺.

Example 6-2 N-({(6S)-1-[4-(Cyclopropylmethoxy)benzyl]-4-hydroxy-6-methyl-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine sodium salt

To a solution of the compound (400 mg) of Reference Example G-3 in ethyl acetate (7.07 mL), the compound of Reference Example A-307 (392 mg), triethylamine (428 mg) and propylphosphonic acid anhydride (cyclic trimer) (50%, solution in ethyl acetate, 1.35 g) were added and the mixture was stirred at room temperature for two hours. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue (708 mg) in ethanol (7.07 mL), cesium carbonate (919 mg) was added and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure and 1 mol/L hydrochloric acid was added to the resulting residue. Extraction was conducted with chloroform and the combined organic layers were dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. To a solution of the resulting residue (650 mg) in methanol (2.82 mL), 2 mol/L sodium hydroxide in aqueous solution (1.41 mL) was added and the mixture was stirred at room temperature for 15 hours. To the reaction mixture, 2 mol/L hydrochloric acid was added and after the resulting mixture was dissolved in N,N-dimethylformamide, purification was conducted by preparative HPLC. To a solution of the resulting purified product (170 mg) in acetone (4.37 mL), 1 mol/L sodium hydroxide in aqueous solution (437 μL) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure and reduced to powder with n-hexane, giving the titled compound as a colorless solid (180 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.26-0.35 (m, 2H) 0.51-0.61 (m, 2H) 1.08 (d, J=6.5 Hz, 3H) 1.13-1.28 (m, 1H) 2.12-2.26 (m, 1H) 2.75-2.93 (m, 1H) 3.51-3.60 (m, 1H) 3.60-3.66 (m, 2H) 3.78 (d, J=7.0 Hz, 2H) 4.05 (d, J=14.9 Hz, 1H) 4.92 (d, J=14.9 Hz, 1H) 6.84-6.92 (m, 2H) 7.17-7.26 (m, 2H) 10.07 (br. s, 1H).

MS ESI/APCI Dual posi: 389 [M+H]⁺.

MS ESI/APCI Dual nega: 387[M−H]⁻.

The compounds of the following Examples 6-3 to 6-36 were synthesized from the compounds of Reference Examples A-308 to A-340 or A-356 and Reference Example G-1, G-2, or G-3 by the method described in Example 6-1 or 6-2 or modifications thereof. The structures of the synthesized compounds and their NMR and MS data are shown in Tables 23-1 to 23-5.

TABLE 23-1 Compound Salt No. Structure Analytical Data information Example 6-3

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.73-1.82 (m, 1 H) 1.87- 1.96 (m, 1 H) 2.20-2.28 (m, 2 H) 2.45-2.56 (m, 2 H) 3.97- 4.01 (m, 2 H) 4.75 (s, 2 H) 7.33-7.37 (m, 3 H) 7.43-7.48 (m, 2 H) 7.61-7.67 (m, 4 H). MS ESI/APCI Dual posi: 407[M + H]⁺. MS ESI/APCI Dual nega: 405[M − H]⁻. Example 6-4

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (d, J = 6.8 Hz, 3 H) 2.68 (t, J = 6.1 Hz, 2 H) 3.62-3.74 (m, 2 H) 3.94- 3.99 (m, 1 H) 4.08-4.17 (m, 1 H) 5.11 (d, J = 15.2 Hz, 1 H) 7.26-7.47 (m, 4 H) 7.51-7.60 (m, 5 H) 8.18 (br. s., 1 H). MS ESI/APCI Dual posi: 395[M + H]⁺. MS ESI/APCI Dual nega: 393[M − H]⁻. Example 6-5

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.10 (d, J = 6.8 Hz, 3 H) 3.13-3.21 (m, 1 H) 3.51 (d, J = 4.7 Hz, 2 H) 4.08 (d, J = 15.5 Hz, 1 H) 4.85 (d, J = 15.5 Hz, 1 H) 7.09-7.16 (m, 2 H) 7.20 (d, J = 8.7 Hz, 1 H) 7.27 (d, J = 8.7 Hz, 2 H) 8.21 (dd, J = 9.0, 2.3 Hz, 1 H) 8.56 (dt, J = 1.7, 0.9 Hz, 1 H) 8.74 (t, J = 4.6 Hz, 1 H). MS ESI/APCI Dual posi: 466[M + H]⁺. MS ESI/APCI Dual nega: 464[M − H]⁻. Na Example 6-6

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.02 (s, 6 H) 3.84 (d, J = 5.4 Hz, 2 H) 4.45 (s, 2 H) 7.04-7.14 (m, 2 H) 7.18 (d, J = 8.7 Hz, 1 H) 7.37 (d, J = 8.7 Hz, 2 H) 8.21 (dd, J = 8.7, 2.3 Hz, 1 H) 8.56 (dd, J = 1.8, 0.9 Hz, 1 H) 8.92 (t, J = 5.6 Hz, 1 H). MS ESI/APCI Dual posi: 480[M + H]⁺. MS ESI/APCI Dual nega: 478[M − H]⁻. Na Example 6-7

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.30 (dd, J = 4.8, 1.6 Hz, 2 H) 0.48-0.60 (m, 2 H) 1.11-1.26 (m, 1 H) 3.15-3.21 (m, 2 H) 3.65 (d, J = 5.0 Hz, 2 H) 3.77 (d, J = 7.0 Hz, 1 H) 4.31 (d, J = 12.9 Hz, 2 H) 6.68 (d, J = 8.5 Hz, 1 H) 6.84 (d, J = 8.5 Hz, 1 H) 6.97 (d, J = 8.5 Hz, 1 H) 7.08 (d, J = 8.5 Hz, 1 H) 8.72-8.80 (m, 1 H). MS ESI/APCI Dual nega: 359[M − H]⁻. Na Example 6-8

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.25-0.35 (m, 2 H) 0.50- 0.60 (m, 2 H) 1.04 (d, J = 6.8 Hz, 3 H) 1.13-1.23 (m, 1 H) 3.02-3.14 (m, 1 H) 3.64-3.94 (m, 4 H) 4.72-4.78 (m, 2 H) 6.67 (d, J = 8.5 Hz, 1 H) 6.72-6.86 (m, 1 H) 6.99 (d, J = 8.5 Hz, 1 H) 7.06-7.13 (m, 1 H) 8.76-8.85 (m, 1 H). MS ESI/APCI Dual posi: 397[M + Na]⁺. MS ESI/APCI Dual nega: 373[M − H]⁻. Na Example 6-9

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.21-0.34 (m, 2 H) 0.49- 0.61 (m, 2 H) 0.94 (s, 7 H) 2.33-2.49 (m, 2 H) 3.67-3.84 (m, 2 H) 4.26-4.41 (m, 2 H) 6.56-6.67 (m, 1 H) 6.69-6.85 (m, 1 H) 7.04-7.15 (m, 1 H) 7.16-7.25 (m, 1 H) 8.90 (br. s., 1 H). MS ESI/APCI Dual posi: 411[M + Na]⁺. MS ESI/APCI Dual nega: 387[M − H]⁻. Na

TABLE 23-2 Compound Salt No. Structure Analytical Data information Example 6-10

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.26-0.37 (m, 2 H) 0.49- 0.64 (m, 2 H) 1.13-1.28 (m, 1 H) 3.10-3.42 (m, 4 H) 3.46-3.55 (m, 2 H) 3.78 (d, J = 7.0 Hz, 2 H) 4.65 (d, J = 6.4 Hz, 1 H) 5.27 (d, J = 15.5 Hz, 1 H) 6.86 (d, J = 8.7 Hz, 2 H) 7.12-7.22 (m, 4 H) 7.23-7.40 (m, 3 H) 10.09 (br. s., 1 H). MS ESI/APCI Dual posi: 451[M + H]⁺. MS ESI/APCI Dual nega: 449[M − H]⁻. Na Example 6-11

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.24-0.37 (m, 2 H) 0.50- 0.61 (m, 2 H) 1.13-1.28 (m, 1 H) 3.12-3.34 (m, 4 H) 3.48 (d, J = 4.4 Hz, 2 H) 3.78 (d, J = 6.8 Hz, 2 H) 4.65 (d, J = 7.6 Hz, 1 H) 5.27 (d, J = 15.1 Hz, 1 H) 6.86 (d, J = 8.7 Hz, 2 H) 7.11- 7.20 (m, 4 H) 7.32 (m, J = 7.6 Hz, 3 H) 10.08 (br. s., 1 H). MS ESI/APCI Dual posi: 451[M + H]⁺. MS ESI/APCI Dual nega: 449[M − H]⁻. Na Example 6-12

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.26-0.35 (m, 2 H) 0.51- 0.61 (m, 2 H) 1.08 (d, J = 6.5 Hz, 3 H) 1.13-1.28 (m, 1 H) 2.12- 2.26 (m, 1 H) 2.75-2.93 (m, 1 H) 3.51-3.60 (m, 1 H) 3.60- 3.66 (m, 2 H) 3.78 (d, J = 7.0 Hz, 2 H) 4.05 (d, J = 14.9 Hz, 1 H) 4.92 (d, J = 14.9 Hz, 1 H) 6.84-6.92 (m, 2 H) 7.17- 7.26 (m, 2 H) 10.07 (br. s, 1 H). MS ESI/APCI Dual posi: 389[M + H]⁺. MS ESI/APCI Dual nega: 387[M − H]⁻. Na Example 6-13

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.28-0.33 (m, 2 H) 0.53- 0.57 (m, 2 H) 1.15-1.24 (m, 1 H) 1.43-1.50 (m, 2 H) 1.85- 1.94 (m, 2 H) 2.83-2.95 (m, 2 H) 3.41-3.50 (m, 4 H) 3.64- 3.70 (m, 2 H) 3.77 (d, J = 6.6 Hz, 2 H) 4.56-4.75 (m, 2 H) 6.82-6.88 (m, 2 H) 7.17-7.23 (m, 2 H). MS ESI/APCI Dual posi: 445[M + H]⁺. MS ESI/APCI Dual nega: 443[M − H]⁻. Na Example 6-14

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.28-0.33 (m, 2 H) 0.53- 0.58 (m, 2 H) 1.15-1.25 (m, 1 H) 2.97-3.10 (m, 2 H) 3.45- 3.52 (m, 2 H) 3.77 (d, J = 7.0 Hz, 2 H) 4.31 (d, J = 7.0 Hz, 2 H) 4.68 (d, J = 7.0 Hz, 2 H) 4.87-4.96 (m, 2 H) 6.84-6.89 (m, 2 H) 7.16-7.21 (m, 2 H). MS ESI/APCI Dual posi: 417[M + H]⁺, 439[M + Na]⁺. MS ESI/APCI Dual nega: 415[M − H]⁻. Na Example 6-15

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.24-0.36 (m, 2 H) 0.49- 0.59 (m, 2 H) 1.10-1.27 (m, 1 H) 2.08 (dd, J = 15.1, 8.2 Hz, 1 H) 2.39-2.49 (m, 1 H) 3.46-3.58 (m, 1 H) 3.70 (d, J = 5.1 Hz, 2 H) 3.75 (d, J = 7.0 Hz, 2 H) 3.84 (d, J = 15.1 Hz, 1 H) 4.83 (d, J = 15.1 Hz, 1 H) 6.76-6.83 (m, 2 H) 6.86 (br. s., 1 H) 7.09 (d, J = 8.5 Hz, 2 H) 7.52-7.61 (m, 1 H) 8.71-8.82 (m, 1 H). MS ESI/APCI Dual nega: 416[M − H]⁻. Na Example 6-16

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.25-0.39 (m, 2 H) 0.50- 0.63 (m, 2 H) 1.14-1.29 (m, 1 H) 2.39-2.70 (m, 2 H) 3.27 (d, J = 15.4 Hz, 1 H) 3.45-3.56 (m, 1 H) 3.73-3.82 (m, 2 H) 4.05- 4.22 (m, 1 H) 4.48-4.66 (m, 2 H) 6.80-6.97 (m, 3 H) 7.14 (d, J = 8.9 Hz, 1 H) 7.29-7.37 (m, 2 H) 8.37 (t, J = 5.8 Hz, 1 H) 11.10 (s, 1 H). MS ESI/APCI Dual posi: 440[M + Na]⁺. MS ESI/APCI Dual nega: 416[M − H]⁻.

TABLE 23-3 Compound Salt No. Structure Analytical Data information Example 6-17

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.04-1.14 (m, 2 H) 1.26 (s, 6 H) 1.66-1.74 (m, 2 H) 1.87-1.97 (m, 1 H) 2.80 (t, J = 11.8 Hz, 2 H) 3.14-3.27 (m, 4 H) 3.45-3.51 (m, 2 H) 4.63-4.70 (m, 2 H) 6.56 (t, J = 4.7 Hz, 1 H) 8.32 (d, J = 4.7 Hz, 2 H). MS ESI/APCI Dual posi: 418[M + H]⁺. MS ESI/APCI Dual nega: 416[M − H]⁻. Na Example 6-18

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.06-0.13 (m, 2 H) 0.40- 0.47 (m, 2 H) 0.89-1.02 (m, 2 H) 1.03-1.13 (m, 1 H) 1.19- 1.30 (m, 6 H) 1.60-1.71 (m, 2 H) 1.77-1.89 (m, 1 H) 2.23 (d, J = 6.6 Hz, 2 H) 2.39-2.49 (m, 1 H) 2.87-2.96 (m, 1 H) 3.09-3.41 (m, 4 H) 3.46-3.53 (m, 3 H) 3.79-3.87 (m, 1 H) 4.35-4.44 (m, 1 H). MS ESI/APCI Dual posi: 422[M + H]⁺. MS ESI/APCI Dual nega: 420[M − H]⁻. Na Example 6-19

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.26-0.35 (m, 2 H) 0.51- 0.61 (m, 2 H) 1.12-1.27 (m, 1 H) 3.13-3.49 (m, 2 H) 3.72- 3.83 (m, 3 H) 3.99-4.08 (m, 2 H) 4.82-4.94 (m, 1 H) 5.13 (d, J = 14.9 Hz, 1 H) 6.84 (d, J = 8.7 Hz, 2 H) 7.14-7.22 (m, 2 H) 7.35-7.43 (m, 1 H) 7.54-7.61 (m, 1 H) 8.37-8.41 (m, 1 H) 8.47-8.52 (m, 1 H) 9.98-10.12 (m, 1 H). MS ESI/APCI Dual posi: 452[M + H]⁺. MS ESI/APCI Dual nega: 450[M − H]⁻. TFA Na Example 6-20

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.26-0.34 (m, 2 H) 0.47- 0.63 (m, 2 H) 1.13-1.31 (m, 1 H) 3.05-3.49 (m, 2 H) 3.67- 3.84 (m, 3 H) 3.96-4.11 (m, 2 H) 4.81-4.96 (m, 1 H) 5.07- 5.15 (m, 1 H) 6.77-6.98 (m, 2 H) 7.08-7.27 (m, 2 H) 7.39 (dd, J = 8.2, 5.1 Hz, 1 H) 7.57 (dd, J = 8.2, 2.0 Hz, 1 H) 8.32- 8.56 (m, 2 H) 9.88-10.17 (m, 1 H). MS ESI/APCI Dual posi: 452[M + H]⁺. MS ESI/APCI Dual nega: 450[M − H]⁻. TFA Na Example 6-21

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.28-0.32 (m, 2 H) 0.52- 0.57 (m, 2 H) 1.14-1.23 (m, 1 H) 1.99-2.14 (m, 1 H) 2.41- 2.53 (m, 1 H) 2.63-2.71 (m, 1 H) 2.82-2.89 (m, 1 H) 3.44- 3.49 (m, 2 H) 3.52-3.62 (m, 1 H) 3.76-3.79 (m, 2 H) 3.81- 3.93 (m, 1 H) 4.92-5.01 (m, 1 H) 6.85-6.90 (m, 2 H) 7.10- 7.15 (m, 2 H) 7.19-7.25 (m, 3 H) 7.27-7.32 (m, 2 H). MS ESI/APCI Dual posi: 465[M + H]⁺. MS ESI/APCI Dual nega: 463[M − H]⁻. Na Example 6-22

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.28-0.32 (m, 2 H) 0.52- 0.57 (m, 2 H) 1.14-1.23 (m, 1 H) 1.99-2.14 (m, 1 H) 2.41- 2.53 (m, 1 H) 2.63-2.71 (m, 1 H) 2.82-2.89 (m, 1 H) 3.44- 3.49 (m, 2 H) 3.52-3.62 (m, 1 H) 3.76-3.79 (m, 2 H) 3.81- 3.93 (m, 1 H) 4.92-5.01 (m, 1 H) 6.85-6.90 (m, 3 H) 7.10- 7.15 (m, 2 H) 7.19-7.25 (m, 3 H) 7.27-7.32 (m, 2 H). MS ESI/APCI Dual posi: 465[M + H]⁺. MS ESI/APCI Dual nega: 463[M − H]⁻. Na Example 6-23

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.24-0.38 (m, 2 H) 0.50- 0.61 (m, 2 H) 0.97-1.68 (m, 11 H) 3.20 (s, 2 H) 3.51 (d, J = 4.5 Hz, 2 H) 3.79 (d, J = 7.0 Hz, 2 H) 4.49 (s, 2 H) 6.82- 6.95 (m, 2 H) 7.15-7.31 (m, 2 H) 10.24 (br. s., 1 H). MS ESI/APCI Dual posi: 443[M + H]⁺. MS ESI/APCI Dual nega: 441[M − H]⁻. Na

TABLE 23-4 Compound Salt No. Structure Analytical Data information Example 6-24

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.23-0.36 (m, 2 H) 0.49- 0.60 (m, 2 H) 0.94-1.71 (m, 11 H) 2.56-2.80 (m, 2 H) 3.45 (d, J = 4.0 Hz, 2 H) 3.77 (d, J = 6.8 Hz, 2 H) 4.63 (br. s., 2 H) 6.83 (d, J = 8.5 Hz, 2 H) 7.18 (d, J = 8.5 Hz, 2 H). MS ESI/APCI Dual posi: 443[M + H]⁺. MS ESI/APCI Dual nega: 441[M − H]⁻. Na Example 6-25

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.17 (s, 6 H) 2.54-2.65 (m, 2 H) 3.46 (d, J = 4.2 Hz, 2 H) 4.38 (s, 2 H) 4.49-4.62 (m, 2 H) 6.88 (d, J = 8.7 Hz, 2 H) 7.22 (d, J = 8.7 Hz, 2 H) 7.31- 7.41 (m, 1 H) 7.45-7.54 (m, 1 H). MS ESI/APCI Dual posi: 406[M + H]⁺. MS ESI/APCI Dual nega: 404[M − H]⁻. Na Example 6-26

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.14-1.27 (m, 8 H) 1.53- 1.64 (m, 3 H) 1.81-1.89 (m, 2 H) 2.46-2.58 (m, 2 H) 2.76- 2.83 (m, 2 H) 3.12-3.28 (m, 2 H) 3.39-3.48 (m, 4 H) 7.20- 7.33 (m, 5 H). MS ESI/APCI Dual posi: 430[M + H]⁺. MS ESI/APCI Dual nega: 428[M − H]⁻. Na Example 6-27

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.24-0.36 (m, 2 H) 0.49- 0.61 (m, 2 H) 0.80 (d, J = 6.8 Hz, 3 H) 0.89 (d, J = 6.8 Hz, 3 H) 1.12-1.28 (m, 1 H) 1.96-2.06 (m, 1 H) 2.25-2.41 (m, 1 H) 2.73 (br. s., 1 H) 3.19-3.32 (m, 1 H) 3.55 (d, J = 4.5 Hz, 2 H) 3.78 (d, J = 7.0 Hz, 2 H) 3.95 (d, J = 15.2 Hz, 1 H) 5.12 (d, J = 15.2 Hz, 1 H) 6.76-6.94 (m, 2 H) 7.11-7.28 (m, 2 H) 9.98 (br. s., 1 H). MS ESI/APCI Dual posi: 417[M + H]⁺. MS ESI/APCI Dual nega: 415[M − H]⁻. Na Example 6-28

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.25-0.34 (m, 2 H) 0.49- 0.60 (m, 2 H) 0.80 (d, J = 6.8 Hz, 3 H) 0.89 (d, J = 6.8 Hz, 3 H) 1.12-1.28 (m, 1 H) 1.93-2.09 (m, 1 H) 2.21-2.41 (m, 1 H) 2.58-2.86 (m, 1 H) 3.19-3.28 (m, 1 H) 3.50 (d, J = 4.4 Hz, 2 H) 3.78 (d, J = 7.0 Hz, 2 H) 3.86-4.02 (m, 1 H) 5.05-5.24 (m, 1 H) 6.86 (d, J = 8.7 Hz, 2 H) 7.20 (d, J = 8.7 Hz, 2 H) 9.97 (br. s., 1 H). MS ESI/APCI Dual posi: 417[M + H]⁺. MS ESI/APCI Dual nega: 415[M − H]⁻. Na Example 6-29

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.23-0.38 (m, 2 H) 0.46- 0.61 (m, 2 H) 1.10-1.28 (m, 7 H) 2.62 (br. s., 2 H) 3.78 (d, J = 5.1 Hz, 2 H) 4.05 (d, J = 7.0 Hz, 2 H) 4.57 (s, 2 H) 6.76 (d, J = 8.5 Hz, 1 H) 7.62 (dd, J = 8.5, 2.5 Hz, 1 H) 8.08 (d, J = 2.5 Hz, 1 H) 10.07 (br. s., 1 H). MS ESI/APCI Dual posi: 404[M + H]⁺. MS ESI/APCI Dual nega: 402[M − H]⁻. Na Example 6-30

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.23-0.38 (m, 2 H) 0.49- 0.63 (m, 2 H) 1.11-1.28 (m, 1 H) 3.23-3.40 (m, 2 H) 3.42- 3.52 (m, 2 H) 3.78 (d, J = 6.8 Hz, 2 H) 3.95-4.15 (m, 1 H) 5.02 (d, J = 15.1 Hz, 2 H) 6.87 (d, J = 8.7 Hz, 2 H) 7.19 (d, J = 8.7 Hz, 2 H) 9.97 (br. s., 1 H). MS ESI/APCI Dual posi: 405[M + H]⁺. MS ESI/APCI Dual nega: 403[M − H]⁻. Na

TABLE 23-5 Compound Salt No. Structure Analytical Data information Example 6-31

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.24-0.37 (m, 2 H) 0.49- 0.61 (m, 2 H) 1.11-1.28 (m, 1 H) 3.25-3.39 (m, 2 H) 3.45 (d, J = 4.4 Hz, 2 H) 3.78 (d, J = 7.0 Hz, 2 H) 3.96-4.13 (m, 1 H) 4.95-5.09 (m, 2 H) 6.82-6.92 (m, 2 H) 7.19 (d, J = 8.5 Hz, 2 H). MS ESI/APCI Dual posi: 405[M + H]⁺. MS ESI/APCI Dual nega: 403[M − H]⁻. Na Example 6-32

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.21-1.37 (m, 6 H) 2.43- 2.72 (m, 3 H) 3.26-3.35 (m, 2 H) 3.50-3.62 (m, 4 H) 4.05- 4.14 (m, 1 H) 4.28-4.37 (m, 1 H) 6.96-7.01 (m, 1 H) 8.38- 8.44 (m, 1 H) 8.73-8.78 (m, 1 H). MS ESI/APCI Dual posi: 390[M + H]⁺. MS ESI/APCI Dual nega: 388[M − H]⁻. TFA Na Example 6-33

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.34-0.39 (m, 2 H) 0.54- 0.59 (m, 2 H) 1.20 (s, 6 H) 1.25-1.33 (m, 1 H) 2.43-2.55 (m, 2 H) 3.37-3.45 (m, 2 H) 4.24 (d, J = 7.4 Hz, 2 H) 4.73- 4.81 (m, 2 H) 7.13-7.19 (m, 1 H) 7.49-7.56 (m, 1 H). MS ESI/APCI Dual posi: 405[M + H]⁺. MS ESI/APCI Dual nega: 403[M − H]⁻. Na Example 6-34

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.24-0.35 (m, 2 H) 0.49- 0.61 (m, 2 H) 1.12-1.27 (m, 1 H) 2.22-2.40 (m, 1 H) 2.64- 2.90 (m, 1 H) 3.21 (s, 3 H) 3.26-3.36 (m, 2 H) 3.61 (d, J = 4.5 Hz, 2 H) 3.54-3.63 (m, 1 H) 3.78 (d, J = 7.0 Hz, 2 H) 3.98- 4.14 (m, 1 H) 4.86-5.08 (m, 1 H) 6.87 (d, J = 8.7 Hz, 2 H) 7.20 (d, J = 8.7 Hz, 2 H). MS ESI/APCI Dual posi: 419[M + H]⁺. MS ESI/APCI Dual nega: 417[M − H]⁻. Na Example 6-35

¹H NMR (600 MHz, DMSO-d₆) δ ppm 0.31-0.36 (m, 2 H) 0.51- 0.58 (m, 2 H) 1.16-1.29 (m, 7 H) 2.44-2.60 (m, 2 H) 3.46 (d, J = 4.1 Hz, 2 H) 4.11 (d, J = 7.0 Hz, 2 H) 4.62 (br. s., 2 H) 8.15 (s, 1 H) 8.22 (s, 1 H). MS ESI/APCI Dual posi: 405[M + H]⁺. MS ESI/APCI Dual nega: 403[M − H]⁻. Na Example 6-36

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.24-0.36 (m, 2 H) 0.48- 0.61 (m, 2 H) 1.07-1.27 (m, 1 H) 2.09 (s, 6 H) 2.13-2.39 (m, 2 H) 2.61-2.90 (m, 2 H) 3.43-3.68 (m, 1 H) 3.70-3.84 (m, 4 H) 3.99-4.16 (m, 1 H) 4.96 (d, J = 14.9 Hz, 1 H) 6.82- 6.94 (m, 2 H) 7.17-7.27 (m, 2 H). MS ESI/APCI Dual posi: 432[M + H]⁺. MS ESI/APCI Dual nega: 430[M − H]⁻. TFA Na

Example 7-1 N-{[9-Benzoyl-1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-en-3-yl]carbonyl}glycine

(1) Synthesis of 2-methyl-2-propanyl 4-[(4-biphenylylmethyl)(3-ethoxy-3-oxopropanoyl)amino]-4-(2-methoxy-2-oxoethyl)-1-piperidinecarboxylate

To a solution of the compound of Reference Example A-344 (3.14 g) and triethylamine (1.50 mL) in ethyl acetate (100 mL), ethyl malonyl chloride (1.22 mL) was added at 0° C. and thereafter the mixture was stirred at room temperature for 30 minutes. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-50:50) to give 2-methyl-2-propanyl 4-[(4-biphenylylmethyl)(3-ethoxy-3-oxopropanoyl)amino]-4-(2-methoxy-2-oxoethyl)-1-piperidinearboxylate as a colorless amorphous mass (3.36 g).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.26 (t, J=7.2 Hz, 3H) 1.38 (s, 9H) 1.68-1.79 (m, 2H) 2.69-2.81 (m, 2H) 2.82-2.96 (m, 2H) 3.29-3.37 (m, 2H) 3.39 (s, 2H) 3.72 (s, 3H) 3.80-4.04 (m, 2H) 4.17 (q, J=7.2 Hz, 2H) 4.73 (s, 2H) 7.27-7.31 (m, 2H) 7.34-7.38 (m, 1H) 7.43-7.47 (m, 2H) 7.56-7.63 (m, 4H).

MS ESI/APCI Dual posi: 575 [M+Na]⁺.

(2) Synthesis of 3-ethyl 9-(2-methyl-2-propanyl) 1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-3,9-dicarboxylate

To a solution in tetrahydrofuran (70 mL) of the mixture (3.35 g) obtained in step (1) above, sodium ethoxide (about 20%, solution in ethanol, 2.5 mL) was added and the mixture was stirred with heating under reflux for 4 hours. After cooling to room temperature, 2 mol/L hydrochloric acid was added and extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-40:60) to give 3-ethyl 9-(2-methyl-2-propanyl) 1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-3,9-dicarboxylate as a colorless amorphous mass (1.87 g).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.41-1.46 (m, 12H) 1.57 (s, 2H) 1.64-1.75 (m, 2H) 1.83-1.99 (m, 2H) 2.75-2.88 (m, 4H) 3.91-4.18 (m, 2H) 4.39-4.45 (m, 2H) 4.64-4.95 (m, 2H) 7.30-7.35 (m, 3H) 7.40-7.44 (m, 2H) 7.49-7.53 (m, 2H) 7.55-7.58 (m, 2H) 14.00-14.18 (m, 1H).

MS ESI/APCI Dual posi: 521 [M+H]⁺, 543 [M+Na]⁺.

MS ESI/APCI Dual nega: 519 [M−H]⁻.

(3) Synthesis of ethyl 1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-3-carboxylate hydrochloride

To the compound (1.70 g) obtained in step (2) above, a solution (10 mL) of 4 mol/L hydrogen chloride in 1,4-dioxane was added and the mixture was stirred at room temperature for 68 hours. After concentrating under reduced pressure, the resulting residue was crystallized with a liquid mixture of diethyl ether and ethyl acetate to give ethyl 1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-3-carboxylate hydrochloride as a colorless solid (983 mg).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.40 (t, J=7.1 Hz, 3H) 1.68-1.82 (m, 2H) 2.55-2.66 (m, 2H) 2.79-2.87 (m, 2H) 2.95-3.12 (m, 2H) 3.36-3.43 (m, 2H) 4.39 (q, J=7.0 Hz, 2H) 4.69-5.04 (m, 2H) 7.28-7.32 (m, 1H) 7.33-7.37 (m, 2H) 7.37-7.41 (m, 2H) 7.46-7.53 (m, 4H) 9.30-9.44 (m, 1H) 9.44-9.57 (m, 1H).

MS ESI/APCI Dual posi: 421 [M+H]⁺, 443 [M+Na]⁺.

MS ESI/APCI Dual nega: 419[M−H]⁻.

(4) Synthesis of ethyl 9-benzoyl-1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-3-carboxylate

To a solution in tetrahydrofuran (6 mL) of the compound (160 mg) obtained in step (3) above, benzoyl chloride (59 mg) and triethylamine (120 mg) were added and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, a saturated aqueous solution of sodium hydrogencarbonate was added and extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol=98:2-80:20) to give ethyl 9-benzoyl-1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-3-carboxylate as a colorless solid (56 mg).

MS ESI/APCI Dual posi: 525 [M+H]⁺.

MS ESI/APCI Dual nega: 523[M−H]⁻.

(5) Synthesis of 2-methyl-2-propanyl N-{[9-benzoyl-1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-en-3-yl]carbonyl}glycinate

To a solution in N,N-dimethylformamide (4.0 mL) of the compound (52 mg) obtained in step (4) above, glycine tert-butyl hydrochloride (29 mg) was added and the mixture was stirred at 90° C. for two hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-methyl-2-propanyl N-{[9-benzoyl-1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-en-3-yl]carbonyl}glycinate as a colorless oil (14 mg).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.45-1.50 (m, 9H) 1.61-1.90 (m, 3H) 2.02-2.17 (m, 1H) 2.75-2.95 (m, 3H) 3.02-3.20 (m, 1H) 3.55-3.75 (m, 1H) 4.00-4.06 (m, 2H) 4.68-4.90 (m, 3H) 7.27-7.46 (m, 10H) 7.51-7.59 (m, 4H) 10.14-10.41 (m, 1H).

MS ESI/APCI Dual posi: 610 [M+H]⁺, 632 [M+Na]⁺.

MS ESI/APCI Dual nega: 608 [M−H]⁻.

(6) Synthesis of the Titled Compound

The compound (14 mg) obtained in step (5) above was used and treated by the same technique as in Example 1-2(2) to give the titled compound as a colorless solid (6 mg).

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.62-1.86 (m, 3H) 2.09 (s, 1H) 2.79-2.96 (m, 3H) 3.04-3.17 (m, 1H) 3.57-3.74 (m, 1H) 4.14-4.22 (m, 2H) 4.63-4.95 (m, 3H) 7.27-7.47 (m, 10H) 7.50-7.61 (m, 4H) 10.16-10.37 (m, 1H).

MS ESI/APCI Dual posi: 554 [M+H]⁺, 576 [M+Na]⁺.

MS ESI/APCI Dual nega: 552[M−H]⁻.

Example 7-2 N-{[9-Benzyl-1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-en-3-yl]carbonyl}glycine trifluoroacetate

(1) Synthesis of ethyl 9-benzyl-1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-3-carboxylate

To a solution in chloroform (3 mL) of the compound (128 mg) obtained in Example 7-1(3), triethylamine (77 mg), N,N-dimethylformamide (1 mL) and benzyl bromide (63 mg) were added successively and the mixture was stirred at 50° C. for two hours. After cooling the reaction mixture to room temperature, water was added to it. Extraction was conducted with chloroform and the combined organic layers were concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol=97:3-80:20) to give ethyl 9-benzyl-1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-3-carboxylate as a colorless solid (32 mg).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=7.1 Hz, 3H) 1.60-1.69 (m, 2H) 2.02-2.15 (m, 4H) 2.71-2.85 (m, 4H) 3.48 (s, 2H) 4.39 (q, J=7.1 Hz, 2H) 4.72-4.96 (m, 2H) 7.23-7.28 (m, 3H) 7.28-7.34 (m, 5H) 7.39-7.43 (m, 2H) 7.46-7.58 (m, 4H).

MS ESI/APCI Dual posi: 511 [M+H]⁺.

MS ESI/APCI Dual nega: 509 [M−H]⁻.

(2) Synthesis of 2-methyl-2-propanyl N-{[9-benzyl-1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-en-3-yl]carbonyl}glycinate

The compound (32 mg) obtained in step (1) above was used and treated by the same technique as in Example 7-1(5) to give 2-methyl-2-propanyl N-{[9-benzyl-1-(4-biphenylylmethyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-en-3-yl]carbonyl}glycinate as a colorless oil (32 mg).

¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9H) 1.60-1.67 (m, 2H) 1.99-2.08 (m, 2H) 2.09-2.19 (m, 2H) 2.70-2.82 (m, 4H) 3.30 (s, 2H) 3.98-4.06 (m, 2H) 4.75-4.86 (m, 2H) 7.22-7.27 (m, 3H) 7.27-7.35 (m, 5H) 7.39-7.44 (m, 2H) 7.48-7.58 (m, 4H) 10.18-10.40 (m, 1H).

MS ESI/APCI Dual posi: 596 [M+H]⁺.

MS ESI/APCI Dual nega: 594 [M−H]⁻.

(3) Synthesis of the Titled Compound

The compound (27 mg) obtained in step (2) above was used and treated by the same technique as in Example 1-2(2) to give the titled compound as a pale yellow solid (31 mg).

¹H NMR (600 MHz, METHANOL-d₄) δ ppm 1.95-2.03 (m, 2H) 2.18-2.28 (m, 2H) 3.00-3.27 (m, 4H) 3.33-3.39 (m, 2H) 3.58 (s, 2H) 4.07-4.13 (m, 2H) 4.26 (s, 2H) 7.27-7.37 (m, 3H) 7.37-7.41 (m, 2H) 7.42-7.49 (m, 5H) 7.53-7.59 (m, 4H).

MS ESI/APCI Dual posi: 540 [M+H]⁺.

Example 7-3 N-[(9-Benzoyl-1-benzyl-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undec-3-en-3-yl)carbonyl]glycine

Instead of the compound obtained in Reference Example A-344, the compound (1.08 g) obtained in Reference Example A-341 was used and treated by the same technique as in Example 7-1 to give the titled compound as a colorless solid (25 mg).

¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.41-1.53 (m, 1H) 1.57-1.70 (m, 1H) 1.74-1.93 (m, 2H) 2.46-2.47 (m, 2H) 2.79-2.92 (m, 2H) 2.98-3.09 (m, 2H) 3.89-4.03 (m, 2H) 4.70-4.82 (m, 2H) 7.21-7.35 (m, 7H) 7.35-7.42 (m, 3H) 9.92-10.20 (m, 1H).

MS ESI/APCI Dual posi: 478 [M+H]⁺, 500 [M+Na]⁺.

MS ESI/APCI Dual nega: 476[M−H]⁻.

Example 8-1 4-Hydroxy-N-[2-(hydroxyamino)-2-oxoethyl]-1-(4-methoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinecarboxamide

Instead of monobenzyl malonate and glycine tert-butyl hydrochloride, the compound (100 mg) obtained in Example 1-48 and hydroxylamine hydrochloride (31 mg) were respectively used and treated by the same technique as in Example G-1(1) to give the titled compound as a colorless amorphous mass (62.2 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.47-2.67 (m, 2H) 3.26-3.37 (m, 2H) 3.79 (s, 3H) 4.00-4.18 (m, 2H) 4.47-4.59 (m, 2H) 6.80-6.93 (m, 2H) 7.14-7.24 (m, 2H) 10.16-10.28 (m, 1H).

MS ESI/APCI Dual posi: 350 [M+H]⁺.

Example 9-1 N-{[4-Hydroxy-1-(4-methoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}-β-alanine

(1) Synthesis of sodium 5-(ethoxycarbonyl)-1-(4-methoxybenzyl)-6-oxo-1,2,3,6-tetrahydro-4-pyridinolate

Instead of the compound obtained in Reference Example A-1, the compound (12.2 g) obtained in Reference Example A-45 was used and treated by the same techniques as in Example 1-1(1) and (2) to give sodium 5-(ethoxycarbonyl)-1-(4-methoxybenzyl)-6-oxo-1,2,3,6-tetrahydro-4-pyridinolate as a solid (12.5 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.10-1.18 (m, 3H) 2.03 (t, J=6.5 Hz, 2H) 3.03 (t, J=6.5 Hz, 2H) 3.72 (s, 3H) 3.94 (q, J=7.0 Hz, 2H) 4.40 (s, 2H) 6.79-6.93 (m, 2H) 7.04-7.27 (m, 2H).

MS ESI/APCI Dual posi: 306 [M+H]⁺, 328 [M+Na]⁺.

MS ESI/APCI Dual nega: 304 [M−H]⁻.

(2) Synthesis of 2-methyl-2-propanyl N-{[4-hydroxy-1-(4-methoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}-β-alaninate

The compound obtained in step (1) above and β alanine tert-butyl hydrochloride (334 mg) rather than glycine tert-butyl hydrochloride were used and treated by the same technique as in Example 1-1(3) to give 2-methyl-2-propanyl N-{[4-hydroxy-1-(4-methoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}-β-alaninate as an oil (518 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9H) 2.46-2.62 (m, 4H) 3.22-3.37 (m, 2H) 3.48-3.72 (m, 2H) 3.80 (s, 3H) 4.47-4.61 (m, 2H) 6.78-6.93 (m, 2H) 9.95-10.41 (m, 2H).

MS ESI/APCI Dual posi: 427 [M+Na]⁺.

MS ESI/APCI Dual nega: 403 [M−H]⁻.

(3) Synthesis of the Titled Compound

The compound (518 mg) obtained in step (2) above was used and treated by the same technique as in Example 1-1(4) to give the titled compound as a colorless solid (283 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.48-2.77 (m, 4H) 3.21-3.37 (m, 2H) 3.58-3.72 (m, 2H) 3.80 (s, 3H) 4.46-4.62 (m, 2H) 6.79-6.94 (m, 2H) 7.11-7.24 (m, 2H) 9.95-10.50 (m, 1H).

MS ESI/APCI Dual posi: 349 [M+H]⁺, 371 [M+Na]⁺.

The compounds of the following Examples 9-2 to 9-4 were synthesized using a commercial grade of the corresponding amines by the method described in Example 9-1 or modifications thereof. The structures of the synthesized compounds and their NMR and MS data are shown in Table 24-1.

TABLE 24-1 Compound Salt No. Structure Analytical Data information Example 9-2

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.90-2.00 (m, 2 H) 2.45 (t, J = 7.1 Hz, 2 H) 2.54-2.63 (m, 2 H) 3.23-3.36 (m, 2 H) 3.37-3.51 (m, 2 H) 3.75-3.85 (m, 3 H) 4.48-4.60 (m, 2 H) 6.81- 6.94 (m, 2 H) 7.14-7.25 (m, 2 H). MS ESI/APCI Dual posi: 363[M + H]⁺. Example 9-3

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.31 (d, J = 7.1 Hz, 3 H) 2.40-2.50 (m, 2 H) 3.22-3.38 (m, 2 H) 3.73 (s, 3 H) 4.06- 4.22 (m, 1 H) 4.49 (s, 3 H) 6.83-6.99 (m, 2 H) 7.15-7.28 (m, 2 H). Na Example 9-4

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.23 (d, J = 6.8 Hz, 3 H) 2.40- 2.50 (m, 2 H) 3.17-3.30 (m, 2 H) 3.73 (s, 3 H) 3.78-3.93 (m, 1 H) 4.48 (s, 2 H) 6.80-6.96 (m, 2 H) 7.16-7.27 (m, 2 H). Na

Example 9-5 N-{[4-Hydroxy-1-(4-methoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}-N-methylglycine

(1) Synthesis of 2-methyl-2-propanyl N-{[4-hydroxy-1-(4-methoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}-N-methylglycinate

To a solution in 1,2-dimethoxyethane (5.0 mL) of the compound (500 mg) obtained in Example 9-1(1), triethylamine (215 mg) and sarcosine tert-butyl hydrochloride (345 mg) were added and the mixture was stirred at 50° C. for 6 hours. After cooling the reaction mixture to room temperature, the insoluble matter was removed by passage through Celite (registered trademark). The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-0:100) to give 2-methyl-2-propanyl N-{[4-hydroxy-1-(4-methoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}-N-methylglycinate as a yellow oil (347 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9H) 2.49 (t, J=6.7 Hz, 2H) 3.06 (s, 3H) 3.31 (t, J=6.7 Hz, 2H) 3.80 (s, 3H) 4.00 (s, 2H) 4.57 (s, 2H) 6.81-6.91 (m, 2H) 7.14-7.25 (m, 2H).

(2) Synthesis of the Titled Compound

The compound (347 mg) obtained in step (1) above was used and treated by the same technique as in Example 1-1(4) to give the titled compound as a colorless solid (116 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.18-2.31 (m, 2H) 2.80 (br. s., 2H) 3.14 (t, J=6.9 Hz, 2H) 3.73 (s, 3H) 4.39 (s, 2H) 6.84-6.90 (m, 2H) 7.12-7.23 (m, 2H).

Example 10-1 N-[(1-{2-[(4-Biphenylylmethyl)amino]-2-oxoethyl}-4-hydroxy-6,6-dimethyl-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine sodium salt

(1) Synthesis of 2-methyl-2-propanyl N-{[1-(2-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}ethyl)-4-hydroxy-6,6-dimethyl-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycinate

Instead of the compound obtained in Reference Example A-1, the compound (19.7 g) obtained in Reference Example A-342 was used and treaded by the same techniques as in Example 1-1(1) to (3) to give 2-methyl-2-propanyl N-{[1-(2-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}ethyl)-4-hydroxy-6,6-dimethyl-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycinate as a pale brown solid (10.9 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.04-0.09 (m, 6H) 0.86-0.93 (m, 9H) 1.31-1.37 (m, 6H) 1.48 (s, 9H) 2.40-2.63 (m, 2H) 3.40-3.58 (m, 2H) 3.64-3.84 (m, 2H) 3.94-4.09 (m, 2H) 10.14-10.39 (m, 1H).

MS ESI/APCI Dual posi: 457 [M+H]⁺.

(2) Synthesis of 2-methyl-2-propanyl N-{[4-hydroxy-1-(2-hydroxyethyl)-6,6-dimethyl-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycinate

The compound (5.25 g) obtained in step (1) above was used and treated by the same technique as in Example 4-1(4) to give 2-methyl-2-propanyl N-{[4-hydroxy-1-(2-hydroxyethyl)-6,6-dimethyl-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycinate as a pale yellow oil (3.90 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.34 (s, 6H) 1.49 (s, 9H) 2.49-2.64 (m, 2H) 3.55-3.66 (m, 2H) 3.71-3.84 (m, 2H) 3.98-4.06 (m, 2H) 9.92-10.55 (m, 1H).

MS ESI/APCI Dual posi: 343 [M+H]⁺.

MS ESI/APCI Dual nega: 341 [M−H]⁻.

(3) Synthesis of 2-methyl-2-propanyl N-{[4-hydroxy-6,6-dimethyl-2-oxo-1-(2-oxoethyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycinate

The compound (3.90 g) obtained in step (2) above was used and treated by the same technique as in Reference Example 19-1 to give 2-methyl-2-propanyl N-{ [4-hydroxy-6,6-dimethyl-2-oxo-1-(2-oxoethyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycinate as a pale yellow solid (2.55 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27-1.33 (m, 6H) 1.43-1.51 (m, 9H) 2.54-2.71 (m, 2H) 3.95-4.18 (m, 4H) 9.52-9.61 (m, 1H) 9.90-10.03 (m, 1H).

MS ESI/APCI Dual posi: 341 [M+H]⁺.

MS ESI/APCI Dual nega: 339 [M−H]⁻.

(4) Synthesis of [4-hydroxy-2,2-dimethyl-5-({2-[(2-methyl-2-propanyl)oxy]-2-oxoethyl}carbamoyl)-6-oxo-3,6-dihydro-1(2H)-pyridinyl]acetic acid

To a suspension in ethanol (40 mL) of the compound (1.93 g) obtained in step (3) above and silver nitrate (1.93 g), a solution of sodium hydroxide (907 mg) in water (26 mL) was added dropwise under cooling with ice and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture, ethyl acetate and 2 mol/L hydrochloric acid were added and the resulting mixture was brought to room temperature. Extraction was conducted with chloroform and the combined organic layers were dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0-85:15, then n-hexane:ethyl acetate=98:2-25:75) to give [4-hydroxy-2,2-dimethyl-5-({2-[(2-methyl-2-propanyl)oxy]-2-oxoethyl}carbamoyl)-6-oxo-3,6-dihydro-1(2H)-pyridinyl]acetic acid as a colorless amorphous mass (1.79 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.31-1.38 (m, 6H) 1.45-1.52 (m, 9H) 2.54-2.70 (m, 2H) 3.97-4.06 (m, 2H) 4.11-4.22 (m, 2H) 9.79-10.54 (m, 1H).

MS ESI/APCI Dual nega: 355 [M−H]⁻.

(5) Synthesis of 2-methyl-2-propanyl N-[(1-{2-[(4-biphenylylmethyl)amino]-2-oxoethyl}-4-hydroxy-6,6-dimethyl-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycinate

Instead of monobenzyl malonate and glycine tert-butyl hydrochloride, the compound (245 mg) obtained in step (4) above and 4-phenylbenzylamine (189 mg) were respectively used and treated by the same technique as in Reference Example G-1(1) to give 2-methyl-2-propanyl N-[(1-{2-[(4-biphenylylmethyl)amino]-2-oxoethyl}-4-hydroxy-6,6-dimethyl-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycinate as a colorless solid (285 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.32-1.37 (m, 6H) 1.45-1.50 (m, 9H) 2.51-2.63 (m, 2H) 3.98-4.06 (m, 2H) 4.09-4.17 (m, 2H) 4.44-4.54 (m, 2H) 6.80-6.90 (m, 1H) 7.29-7.38 (m, 3H) 7.39-7.48 (m, 2H) 7.51-7.62 (m, 4H) 9.85-10.62 (m, 1H).

MS ESI/APCI Dual posi: 544 [M+Na]⁺.

MS ESI/APCI Dual nega: 520 [M−H]⁻.

(6) Synthesis of the titled compound

The compound (285 mg) obtained in step (5) above was used and treated by the same techniques as in Example 1-3(2) and (3) to give the titled compound as a pale yellow solid (237 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.23 (s, 6H) 2.54-2.71 (m, 2H) 3.46 (d, J=4.4 Hz, 2H) 4.01 (s, 2H) 4.33 (d, J=6.1 Hz, 2H) 7.29-7.39 (m, 3H) 7.40-7.50 (m, 2H) 7.56-7.70 (m, 4H) 8.27-8.44 (m, 1H) 9.86-10.12 (m, 1H).

The compounds of the following Examples 10-2 and 10-4 were synthesized using a commercial grade of the corresponding amines by the method described in Example 10-1 or a modification thereof. The structures of the synthesized compounds and their NMR and MS data are shown in Table 25-1.

TABLE 25-1 Compound Salt No. Structure Analytical Data information Example 10-2

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.25 (s, 6 H) 2.67-2.83 (m, 2 H) 3.95-4.05 (m, 4 H) 4.30-4.45 (m, 2 H) 7.40-7.55 (m, 2 H) 7.61-7.74 (m, 2 H) 8.28-8.70 (m, 1 H) 9.84-10.28 (m, 1 H) 12.56-13.06 (m, 1 H). Example 10-4

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.13-1.30 (m, 6 H) 2.40- 2.60 (m, 2 H) 2.76-3.04 (m, 3 H) 3.41-3.54 (m, 2 H) 4.18-4.35 (m, 2 H) 4.44-4.68 (m, 2 H) 7.10-7.33 (m, 4 H) 7.33-7.45 (m, 1 H) 9.71-10.24 (m, 1 H). MS ESI/APCI Dual posi: 444[M + Na]⁺. MS ESI/APCI Dual nega: 420[M − H]⁻. Na

Example 11-1 N-({1-[1-(4′-Fuoro-4-biphenylyl)-2-hydroxyethyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine

(1) Synthesis of methyl N-({1-[2-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-1-(4-iodophenyl)ethyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate

Instead of the compound obtained in Reference Example A-1 and glycine tert-butyl hydrochloride, the compound (1.40 g) obtained in Reference Example B-19 and glycine methyl hydrochloride (442 mg) were respectively used and treated by the same techniques as in Example 1-1(1) to (3) to give methyl N-({1-[2-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}-1-(4-iodophenyl)ethyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate as a pale brown solid (1.40 g).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.09 (s, 6H) 0.87 (s, 9H) 2.39-2.62 (m, 2H) 3.05-3.21 (m, 1H) 3.33-3.50 (m, 1H) 3.78 (s, 3H) 3.99-4.21 (m, 4H) 5.55-5.78 (m, 1H) 7.04-7.16 (m, 2H) 7.61-7.74 (m, 2H).

MS ESI/APCI Dual posi: 589 [M+H]⁺.

MS ESI/APCI Dual nega: 587 [M−H]⁻.

(2) Synthesis of methyl N-({4-hydroxy-1-[2-hydroxy-1-(4-iodophenyl)ethyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate

To a solution in ethyl acetate (67 mL) of the compound (1.32 g) obtained in step (1) above, a solution (12.3 mL) of 4 mol/L hydrogen chloride in 1,4-dioxane was added and the mixture was stirred at room temperature for an hour. Water was then added under cooling with ice. Extraction was conducted with ethyl acetate and the organic layer was washed with saturated brine. The washed organic layer was dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-0:100) to give methyl N-({4-hydroxy-1-[2-hydroxy-1-(4-iodophenyl)ethyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycinate as a pale yellow amorphous mass (880 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.35-2.62 (m, 2H) 2.99-3.18 (m, 1H) 3.26-3.46 (m, 1H) 3.77 (s, 3H) 3.94-4.22 (m, 4H) 5.58-5.80 (m, 1H) 6.95-7.13 (m, 2H) 7.57-7.78 (m, 2H) 9.95-10.56 (m, 1H).

MS ESI/APCI Dual posi: 475 [M+H]⁺.

MS ESI/APCI Dual nega: 473 [M−H]⁻.

(3) Synthesis of methyl N-{[7-hydroxy-3-(4-iodophenyl)-2,3,6,8a-tetrahydro-5H-[1,3]oxazolo[3,2-a]pyridin-8-yl]carbonyl}glycinate

To a solution in acetonitrile (14.8 mL) of the compound (880 mg) obtained in step (2) above, propylphosphonic acid anhydride (cyclic trimer) (50%, solution in ethyl acetate, 5.91 g) was added and the solvent was immediately concentrated under reduced pressure. To the resulting residue, acetonitrile (14.8 mL) was added and the mixture was stirred at 90° C. for three hours. The reaction mixture was concentrated under reduced pressure and chloroform was added to the concentrate. With the solvent being distilled off under reduced pressure, the crude product was adsorbed on diatomaceous earth. The crude product adsorbed on the diatomaceous earth was purified by NH silica gel column chromatography (chlorform:methanol=100:0-95:5) to give methyl N-{[7-hydroxy-3-(4-iodophenyl)-2,3,6,8a-tetrahydro-5H-[1,3]oxazolo[3,2-a]pyridin-8-yl]carbonyl}glycinate as a colorless solid (690 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.51-2.74 (m, 2H) 3.11-3.37 (m, 2H) 3.74 (s, 3H) 4.12 (d, J=5.6 Hz, 2H) 4.53 (dd, J=9.2, 8.5 Hz, 1H) 4.75 (t, J=8.5 Hz, 1H) 4.97-5.22 (m, 1H) 7.02-7.12 (m, 2H) 7.73-7.83 (m, 2H) 9.59 (t, J=5.4 Hz, 1H).

MS ESI/APCI Dual posi: 457 [M+H]⁺, 479 [M+Na]⁺.

(4) Synthesis of methyl N-{[3-(4′-fluoro-4-biphenylyl)-7-hydroxy-2,3,6,8a-tetrahydro-5H-[1,3]oxazolo[3,2-a]pyridin-8-yl]carbonyl}glycinate

A mixture of the compound (100 mg) obtained in step (3) above, 4-fluorophenylboronic acid (66 mg), palladium(II) acetate (6.6 mg), tri(2-methylphenyl)phosphine (26 mg), potassium carbonate (186 mg), methanol (4.4 mL) and toluene (2.2 mL) was stirred in a sealed tube at 90° C. for 70 minutes. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-0:100, then chloroform:methanol=100:0-85:15) to give methyl N-{[3-(4′-fluoro-4-biphenylyl)-7-hydroxy-2,3,6,8a-tetrahydro-5H-[1,3]oxazolo[3,2-a]pyridin-8-yl]carbonyl}-glycinate as a pale brown solid (100 mg).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.56-2.76 (m, 2H) 3.18-3.50 (m, 2H) 3.74 (s, 3H) 4.10-4.17 (m, 2H) 4.54-4.68 (m, 1H) 4.88 (t, J=8.5 Hz, 1H) 5.06-5.22 (m, 1H) 7.09-7.22 (m, 2H) 7.36-7.47 (m, 2H) 7.50-7.66 (m, 4H) 9.69 (t, J=5.5 Hz, 1H).

MS ESI/APCI Dual posi: 425 [M+H]⁺, 447 [M+Na]⁺.

(5) Synthesis of the Titled Compound

To a solution in tetrahydrofuran (2.4 mL) and methanol (2.4 mL) of the compound (100 mg) obtained in step (4) above, 1 mol/L sodium hydroxide in aqueous solution (471 μL) was added and the mixture was stirred at room temperature for 13 hours. The precipitate was recovered by filtration and dissolved in ethyl acetate and 4 mol/L hydrochloric acid. The organic layer was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC. To a solution of the resulting purified product (45.0 mg) in acetone (2 mL), 1 mol/L sodium hydroxide in aqueous solution (105 μL) was added and the mixture was stirred at room temperature. The precipitate was recovered by filtration to give the titled compound as a colorless solid (40 mg).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.40-2.50 (m, 2H) 3.00-3.22 (m, 1H) 3.37-3.51 (m, 2H) 3.83-4.03 (m, 2H) 5.11 (br. s., 1H) 5.68 (br. s., 1H) 7.21-7.35 (m, 2H) 7.35-7.48 (m, 2H) 7.55-7.76 (m, 4H).

MS ESI/APCI Dual posi: 429 [M+H]⁺.

MS ESI/APCI Dual nega: 427 [M−H]⁻.

Reference Example X-1 Synthesis of (5S)-1-(biphenyl-4-ylmethyl)-N-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-carboxamide and determination of its absolute configuration by X-ray crystallography

To a solution in N,N-dimethylformamide (1.00 mL) of the compound (60.8 mg) obtained in Example 5-1, 4-bromoaniline (39.0 mg), propylphosphonic acid anhydride (cyclic trimer) (50%, solution in N,N-dimethylformamide, 135 μL) and triethylamine (64.0 μL) were added and the mixture was stirred overnight at room temperature. To the reaction mixture, 4-bromoaniline (39.0 mg), propylphosphonic acid anhydride (cyclic trimer) (50%, solution in N,N-dimethylformamide, 135 μL) and triethylamine (64.0 μL) were further added and the mixture was stirred at room temperature for three hours. The reaction mixture was purified by preparative HPLC to give the residue (43.2 mg). The resulting residue was crystallized with a liquid mixture of n-hexane, diethyl ether, and ethyl acetate to give the titled compound as a colorless solid (25.8 mg, 95.5% ee). Part of the resulting solid was recrystallized with a liquid mixture of chloroform and methanol and the resulting acicular crystal was used in X-ray crystallography. As the result, the 2-oxo-1,2,5,6-tetrahydropyridine ring of the crystal was determined to have an absolute configuration (S) at position 5.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.09-1.24 (m, 3H) 2.69-2.86 (m, 1H) 3.10 (dd, J=12.5, 8.2 Hz, 1H) 3.44 (dd, J=12.5, 5.8 Hz, 1H) 4.11-4.18 (m, 2H) 4.60-4.73 (m, 2H) 7.30-7.39 (m, 3H) 7.40-7.48 (m, 6H) 7.53-7.62 (m, 4H) 8.14-8.24 (m, 1H) 10.46-10.58 (m, 1H).

MS ESI/APCI Dual posi: 548 [M+H]⁺.

MS ESI/APCI Dual nega: 546 [M−H]⁻.

Optical HPLC retention time: 11.041 min.

Reference Example X-2 Synthesis of (5R)-1-(biphenyl-4-ylmethyl)-N-{2-[(4-bromophenyl)amino]-2-oxoethyl}-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydropyridin-3-carboxamide and determination of its absolute configuration by X-ray crystallography

The compound (54.8 mg) obtained in Example 5-2 was used and treated by the same technique as in Reference Example X-1 to give the titled compound as a colorless solid (33.1 mg, 93.8% ee). By subsequent X-ray crystallography, the 2-oxo-1,2,5,6-tetrahydropyridine ring of the crystal was determined to have an absolute configuration (R) at position 5.

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.09-1.24 (m, 3H) 2.55-2.82 (m, 1H) 3.10 (dd, J=12.5, 8.1 Hz, 1H) 3.44 (dd, J=12.5, 5.9 Hz, 1H) 4.12-4.18 (m, 2H) 4.59-4.73 (m, 2H) 7.31-7.40 (m, 3H) 7.40-7.49 (m, 6H) 7.54-7.62 (m, 4H) 7.97-8.23 (m, 1H) 10.46-10.59 (m, 1H).

MS ESI/APCI Dual posi: 548 [M+H]⁺.

MS ESI/APCI Dual nega: 546 [M−H]⁻.

Optical HPLC retention time: 12.096 min.

The PHD2 inhibitory activities of compounds of the present invention were determined in accordance with Tests 1 and 2 described below.

Test 1

(1) Expression and Preparation of Human PHD2

Human PHD2 was expressed in insect cells (HighFive cells). A registered sequence of human PHD2 (NM_022051) was introduced into the pFastBacl vector (Invitrogen), and the sequence was verified. The vector was introduced into Sf9 insect cells (Invitrogen) to acquire human PHD2 baculovirus. HighFive insect cells (Invitrogen) were infected with this recombinant virus and cultured at 27° C. for 72 hours; thereafter, a cell lysis solution containing various protease inhibitors was added and the cells were disrupted to form a suspension. The suspension of disrupted cells was centrifuged at 4° C. and 100,000×g for 30 minutes and the supernatant was recovered as a cell lysate. Analysis by Western blotting confirmed that the human PHD2 protein was expressed only in the lysate of cells infected with the PHD2 baculovirus.

-   -   (2) Measurement of Human PHD2 Inhibitory Activity

The activity of human PHD2 enzyme was measured with a substrate which is a 19-residue partial peptide based on the sequence of HIF-1α. Specifically, the conversion of 2-oxoglutarate to succinic acid which would occur simultaneously with the hydroxylation of a proline residue in the peptide with the PHD2 enzyme was utilized. To be more specific, [¹⁴C]-2-oxogiutarate was added to the reaction system to initiate an enzymatic reaction and the [¹⁴C]-2-oxoglutarate remaining after the reaction was bound to 2,4-dinitrophenylhydrazine (DNPH), with the resulting precipitate being removed by passage through a filter. Subsequently, radiation counting was conducted on the resulting [¹⁴C]-succinic acid.

The enzyme and the substrate were each diluted with a 20 mM tris-hydrochloric acid buffer (pH 7.5) containing 6.67 mM KCl, 2 mM MgCl₂, 13.3 μM iron sulfate, 2.67 mM ascorbic acid, and 1.33 mM DTT, whereas each test compound was diluted with dimethyl sulfoxide (DMSO).

A test compound, HIF-1αpeptide and [¹⁴C]-2-oxoglutarate were preliminarily added onto 96-well plates and reaction was initiated by adding a human PHD2 enzyme solution (4 μg/well). After 15-min incubation at 37° C., a DNPH-containing quench solution was added and the mixture was allowed to stand at room temperature for 30 minutes. Thereafter, an excess of non-radiolabelled 2-oxoglutarate was added and the mixture was allowed to stand at room temperature for 60 minutes. The resulting precipitate was removed by passage through a filter and the radiation count on the [¹⁴C]-succinic acid was quantified (with MicroBeta). Radiation counting was conducted for each well and the human PHD2 inhibitory activity of each test compound was calculated on the basis of the values for the substrate-free group and the test compound-free group.

(3) Results

The inhibition data of human PHD2 for the test compounds (%, test compound's concentration was 1 μM) are shown in the following Tables 26-1 to 26-3.

TABLE 26-1 Compound Percent inhibition No. (% at 1 μM) Ex. 1-1 78 Ex. 1-2 94 Ex. 1-3 74 Ex. 1-4 104 Ex. 1-5 52 Ex. 1-6 50 Ex. 1-7 54 Ex. 1-8 54 Ex. 1-9 88 Ex. 1-10 93 Ex. 1-11 95 Ex. 1-12 88 Ex. 1-13 64 Ex. 1-14 21 Ex. 1-15 72 Ex. 1-16 94 Ex. 1-17 84 Ex. 1-18 88 Ex. 1-19 86 Ex. 1-20 93 Ex. 1-21 72 Ex. 1-22 95 Ex. 1-23 84 Ex. 1-24 74 Ex. 1-25 72 Ex. 1-26 90 Ex. 1-27 75 Ex. 1-28 94 Ex. 1-29 81 Ex. 1-30 77 Ex. 1-31 89 Ex. 1-32 78 Ex. 1-33 72 Ex. 1-34 58 Ex. 1-35 81 Ex. 1-36 83 Ex. 1-37 87 Ex. 1-38 48 Ex. 1-39 76 Ex. 1-40 79 Ex. 1-41 89 Ex. 1-42 90 Ex. 1-43 74 Ex. 1-44 87 Ex. 1-45 82 Ex. 1-46 78 Ex. 1-47 77 Ex. 1-48 67 Ex. 1-49 55 Ex. 1-50 77 Ex. 1-51 58 Ex. 1-52 58 Ex. 1-53 78 Ex. 1-54 60 Ex. 1-55 75 Ex. 1-56 70 Ex. 1-57 58 Ex. 1-58 67 Ex. 1-59 41 Ex. 1-60 66 Ex. 1-61 58 Ex. 1-62 65 Ex. 1-63 43 Ex. 1-64 80 Ex. 1-65 84 Ex. 1-66 80 Ex. 1-67 84 Ex. 1-68 67 Ex. 1-69 85 Ex. 1-70 104 Ex. 1-71 81 Ex. 1-72 98 Ex. 1-73 99 Ex. 1-74 80 Ex. 1-75 54 Ex. 1-76 40 Ex. 1-77 74 Ex. 1-78 70 Ex. 1-79 64 Ex. 1-80 76 Ex. 1-81 72 Ex. 1-82 51 Ex. 1-83 54 Ex. 1-84 42 Ex. 1-85 61 Ex. 1-86 48 Ex. 1-87 46 Ex. 1-88 44 Ex. 1-89 69 Ex. 1-90 58 Ex. 1-91 85 Ex. 1-92 69 Ex. 1-93 80 Ex. 1-94 84 Ex. 1-95 85 Ex. 1-96 82 Ex. 1-97 89 Ex. 1-98 88 Ex. 1-99 71 Ex. 1-100 64 Ex. 1-101 60 Ex. 1-102 67 Ex. 1-103 76 Ex. 1-104 87 Ex. 1-105 78 Ex. 1-106 66 Ex. 1-107 67 Ex. 1-108 60 Ex. 1-109 70 Ex. 1-110 82 Ex. 1-111 68 Ex. 1-112 68 Ex. 1-113 79 Ex. 1-114 36 Ex. 1-115 49 Ex. 1-116 82 Ex. 1-117 83 Ex. 1-118 77 Ex. 1-119 85 Ex. 1-120 69 Ex. 1-121 66 Ex. 1-122 65 Ex. 1-123 90 Ex. 1-124 72 Ex. 1-125 98 Ex. 1-126 97 Ex. 1-127 92 Ex. 1-128 88 Ex. 1-129 71 Ex. 1-130 89 Ex. 1-131 93 Ex. 1-132 103 Ex. 1-133 104 Ex. 1-134 86 Ex. 1-135 78 Ex. 1-136 91 Ex. 1-137 78 Ex. 1-138 83 Ex. 1-139 72 Ex. 1-140 79 Ex. 1-141 64 Ex. 1-142 54 Ex. 1-143 41 Ex. 1-144 76 Ex. 1-145 88 Ex. 1-146 69 Ex. 1-147 84 Ex. 1-148 78 Ex. 1-149 74 Ex. 1-150 63

TABLE 26-2 Compound Percent inhibition No. (% at 1 μM) Ex. 1-151 57 Ex. 1-152 82 Ex. 1-153 64 Ex. 1-154 77 Ex. 1-155 82 Ex. 1-156 70 Ex. 1-157 67 Ex. 1-158 67 Ex. 1-159 78 Ex. 1-160 74 Ex. 1-161 62 Ex. 1-162 78 Ex. 1-163 84 Ex. 1-164 49 Ex. 1-165 42 Ex. 1-166 82 Ex. 1-167 80 Ex. 1-168 51 Ex. 1-169 28 Ex. 1-170 35 Ex. 1-171 81 Ex. 1-172 77 Ex. 1-173 64 Ex. 1-174 59 Ex. 1-175 32 Ex. 1-176 74 Ex. 1-177 93 Ex. 1-178 81 Ex. 1-179 44 Ex. 1-180 54 Ex. 1-181 73 Ex. 1-182 77 Ex. 1-183 39 Ex. 1-184 59 Ex. 1-185 69 Ex. 1-186 64 Ex. 1-187 47 Ex. 1-188 44 Ex. 1-189 53 Ex. 1-190 84 Ex. 1-191 38 Ex. 1-192 48 Ex. 1-193 67 Ex. 1-194 54 Ex. 1-195 52 Ex. 1-196 41 Ex. 1-197 66 Ex. 1-198 70 Ex. 1-199 65 Ex. 1-200 98 Ex. 1-201 67 Ex. 1-202 58 Ex. 1-203 61 Ex. 1-204 69 Ex. 1-205 104 Ex. 1-206 95 Ex. 1-207 92 Ex. 1-208 90 Ex. 1-209 102 Ex. 1-210 59 Ex. 1-211 76 Ex. 1-212 82 Ex. 1-213 88 Ex. 1-214 89 Ex. 1-215 85 Ex. 1-216 75 Ex. 1-217 52 Ex. 1-218 52 Ex. 1-219 69 Ex. 1-220 72 Ex. 1-221 66 Ex. 1-222 90 Ex. 1-223 90 Ex. 1-224 80 Ex. 1-225 100 Ex. 1-227 76 Ex. 1-228 71 Ex. 1-229 74 Ex. 1-230 96 Ex. 1-231 65 Ex. 1-232 89 Ex. 1-233 91 Ex. 1-234 61 Ex. 1-235 91 Ex. 1-236 84 Ex. 1-237 74 Ex. 1-238 92 Ex. 1-239 74 Ex. 1-240 91 Ex. 1-241 97 Ex. 1-242 100 Ex. 1-243 76 Ex. 1-244 47 Ex. 1-245 80 Ex. 1-246 97 Ex. 1-247 81 Ex. 1-249 103 Ex. 1-250 80 Ex. 1-251 90 Ex. 1-252 104 Ex. 1-253 45 Ex. 1-254 103 Ex. 1-255 99 Ex. 1-256 101 Ex. 1-257 95 Ex. 1-258 94 Ex. 1-259 92 Ex. 1-260 95 Ex. 1-261 99 Ex. 1-262 88 Ex. 1-263 81 Ex. 1-264 83 Ex. 1-265 98 Ex. 1-266 83 Ex. 1-267 81 Ex. 1-268 78 Ex. 1-269 85 Ex. 1-270 88 Ex. 1-271 91 Ex. 1-272 65 Ex. 1-273 99 Ex. 1-274 92 Ex. 1-275 85 Ex. 1-276 93 Ex. 1-277 108 Ex. 1-278 93 Ex. 1-279 90 Ex. 1-280 109 Ex. 1-281 70 Ex. 1-282 101 Ex. 1-283 99 Ex. 1-284 107 Ex. 1-285 106 Ex. 1-286 95 Ex. 1-287 94 Ex. 1-288 90 Ex. 1-289 95 Ex. 1-290 63 Ex. 1-291 75 Ex. 1-292 83 Ex. 1-293 35 Ex. 1-294 51 Ex. 1-295 63 Ex. 1-296 100 Ex. 1-297 86 Ex. 1-298 84 Ex. 1-299 47 Ex. 1-300 30 Ex. 1-301 56 Ex. 1-302 61

TABLE 26-3 Compound Percent inhibition No. (% at 1 μM) Ex. 1-303 102 Ex. 1-304 35 Ex. 1-305 94 Ex. 1-306 94 Ex. 1-307 51 Ex. 2-1 93 Ex. 2-6 68 Ex. 2-7 88 Ex. 2-8 87 Ex. 2-9 78 Ex. 2-10 84 Ex. 2-11 93 Ex. 2-12 93 Ex. 2-13 92 Ex. 2-14 98 Ex. 2-15 97 Ex. 2-16 102 Ex. 2-17 94 Ex. 2-18 98 Ex. 2-19 96 Ex. 2-20 102 Ex. 2-21 88 Ex. 2-22 95 Ex. 2-23 88 Ex. 2-24 91 Ex. 2-25 92 Ex. 2-26 90 Ex. 2-27 100 Ex. 2-28 90 Ex. 2-29 101 Ex. 2-30 103 Ex. 3-1 102 Ex. 3-2 87 Ex. 4-1 58 Ex. 4-2 77 Ex. 5-1 93 Ex. 5-2 92

Test 2

(1) Expression and Preparation of Human PHD2

Human PHD2 was expressed in human cells (293FT cells). A registered sequence of human PHD2 (NM_(—)022051) was introduced into pcDNA3.1/Hygro(+) vector (Invitrogen), and the sequence was verified. The vector was introduced into 293FT cells (Invitrogen) which were cultured at 37° C. in the presence of 5% CO₂ gas for 48 hours; thereafter, a cell lysis solution containing various protease inhibitors was added and the cells were disrupted to form a suspension. The suspension of disrupted cells was centrifuged at 4° C. and 100,000×g for 30 minutes and the supernatant was recovered as a cell lysate. Analysis by Western blotting confirmed that the human PHD2 protein was expressed in the cell lysate.

(2) Measurement of Human PHD2 Inhibitory Activity

The activity of human PHD2 enzyme was measured with a substrate which is a 19-residue partial peptide based on the sequence of HIF-1α; specifically, the hydroxylation of a proline residue in the peptide was measured by FP (Fluorescence Polarization).

The enzyme and the substrate were each diluted with a 50 mM tris-hydrochloric acid buffer (pH 7.5) containing 12.5 mM KCl, 3.75 mM MgCl₂, 25 μM iron sulfate, 5 mM ascorbic acid, and 2.5 mM DTT, whereas each test compound was diluted with dimethyl sulfoxide (DMSO).

A test compound and the substrate solution were preliminarily added onto 384-well plates and reaction was initiated by adding a human PHD2 enzyme solution (40 ng/well). After 20-min incubation at 30° C., an EDTA-containing quench solution was added and the amount of the proline residues hydroxylated via binding to an added HIF-OH antibody solution was quantified by fluorescence polarization.

The fluorescence polarization of each well was measured and the human PHD2 inhibitory activity of each test compound was calculated on the basis of the values for the test compound-free group.

(3) Results

The inhibition data of human PHD2 for the test compounds (%, test compound's concentration was 1 μM) are shown in the following Tables 27-1 to 27-4. For representative compounds, their 10₅₀ values (nM) are shown in the following Table 28-1.

TABLE 27-1 Compound Percent inhibition No. (% at 1 μM) Ex. 1-1 94 Ex. 1-2 92 Ex. 1-3 78 Ex. 1-4 96 Ex. 1-5 76 Ex. 1-6 57 Ex. 1-7 68 Ex. 1-8 87 Ex. 1-9 93 Ex. 1-10 92 Ex. 1-11 93 Ex. 1-12 93 Ex. 1-13 81 Ex. 1-14 36 Ex. 1-15 86 Ex. 1-16 92 Ex. 1-17 85 Ex. 1-18 86 Ex. 1-19 81 Ex. 1-20 93 Ex. 1-21 73 Ex. 1-22 85 Ex. 1-23 82 Ex. 1-24 84 Ex. 1-25 76 Ex. 1-26 94 Ex. 1-27 89 Ex. 1-28 92 Ex. 1-29 86 Ex. 1-30 83 Ex. 1-31 89 Ex. 1-32 82 Ex. 1-33 84 Ex. 1-34 75 Ex. 1-35 90 Ex. 1-36 85 Ex. 1-37 89 Ex. 1-38 66 Ex. 1-39 86 Ex. 1-40 91 Ex. 1-41 90 Ex. 1-42 94 Ex. 1-43 79 Ex. 1-44 91 Ex. 1-45 88 Ex. 1-46 84 Ex. 1-47 81 Ex. 1-48 79 Ex. 1-49 55 Ex. 1-50 83 Ex. 1-51 73 Ex. 1-52 78 Ex. 1-53 78 Ex. 1-54 71 Ex. 1-55 79 Ex. 1-56 69 Ex. 1-57 83 Ex. 1-58 71 Ex. 1-59 54 Ex. 1-60 76 Ex. 1-61 71 Ex. 1-62 68 Ex. 1-63 69 Ex. 1-64 81 Ex. 1-65 85 Ex. 1-66 77 Ex. 1-67 89 Ex. 1-68 66 Ex. 1-69 81 Ex. 1-70 95 Ex. 1-71 85 Ex. 1-72 89 Ex. 1-73 90 Ex. 1-74 86 Ex. 1-75 84 Ex. 1-76 79 Ex. 1-77 85 Ex. 1-78 78 Ex. 1-79 71 Ex. 1-80 88 Ex. 1-81 64 Ex. 1-82 77 Ex. 1-83 73 Ex. 1-84 67 Ex. 1-85 65 Ex. 1-86 71 Ex. 1-87 86 Ex. 1-88 55 Ex. 1-89 72 Ex. 1-90 63 Ex. 1-91 94 Ex. 1-92 66 Ex. 1-93 81 Ex. 1-94 92 Ex. 1-95 91 Ex. 1-96 86 Ex. 1-97 91 Ex. 1-98 88 Ex. 1-99 92 Ex. 1-100 84 Ex. 1-101 86 Ex. 1-102 83 Ex. 1-103 82 Ex. 1-104 94 Ex. 1-105 83 Ex. 1-106 72 Ex. 1-107 90 Ex. 1-108 87 Ex. 1-109 77 Ex. 1-110 84 Ex. 1-111 80 Ex. 1-112 90 Ex. 1-113 84 Ex. 1-114 83 Ex. 1-115 83 Ex. 1-116 84 Ex. 1-117 92 Ex. 1-118 87 Ex. 1-119 84 Ex. 1-120 82 Ex. 1-121 71 Ex. 1-122 76 Ex. 1-123 93 Ex. 1-124 79 Ex. 1-125 97 Ex. 1-126 98 Ex. 1-127 95 Ex. 1-128 84 Ex. 1-129 80 Ex. 1-130 90 Ex. 1-131 96 Ex. 1-132 94 Ex. 1-133 97 Ex. 1-134 85 Ex. 1-135 78 Ex. 1-136 88 Ex. 1-137 92 Ex. 1-138 97 Ex. 1-139 78 Ex. 1-140 85 Ex. 1-141 62 Ex. 1-142 52 Ex. 1-143 65 Ex. 1-144 85 Ex. 1-145 83 Ex. 1-146 70 Ex. 1-147 88 Ex. 1-148 82 Ex. 1-149 74 Ex. 1-150 71

TABLE 27-2 Compound Percent inhibition No. (% at 1 μM) Ex. 1-151 63 Ex. 1-152 83 Ex. 1-153 63 Ex. 1-154 81 Ex. 1-155 83 Ex. 1-156 80 Ex. 1-157 73 Ex. 1-158 75 Ex. 1-159 90 Ex. 1-160 85 Ex. 1-161 62 Ex. 1-162 77 Ex. 1-163 90 Ex. 1-164 66 Ex. 1-165 55 Ex. 1-166 86 Ex. 1-167 88 Ex. 1-168 69 Ex. 1-169 43 Ex. 1-170 45 Ex. 1-171 82 Ex. 1-172 79 Ex. 1-173 78 Ex. 1-174 74 Ex. 1-175 56 Ex. 1-176 80 Ex. 1-177 92 Ex. 1-178 92 Ex. 1-179 49 Ex. 1-180 65 Ex. 1-181 83 Ex. 1-182 71 Ex. 1-183 50 Ex. 1-184 60 Ex. 1-185 81 Ex. 1-186 77 Ex. 1-187 74 Ex. 1-188 63 Ex. 1-189 60 Ex. 1-190 85 Ex. 1-191 45 Ex. 1-192 49 Ex. 1-193 57 Ex. 1-194 57 Ex. 1-195 57 Ex. 1-196 48 Ex. 1-197 78 Ex. 1-198 79 Ex. 1-199 75 Ex. 1-200 99 Ex. 1-201 73 Ex. 1-202 69 Ex. 1-203 69 Ex. 1-204 79 Ex. 1-205 98 Ex. 1-206 93 Ex. 1-207 93 Ex. 1-208 85 Ex. 1-209 95 Ex. 1-210 42 Ex. 1-211 79 Ex. 1-212 85 Ex. 1-213 88 Ex. 1-214 90 Ex. 1-215 86 Ex. 1-216 73 Ex. 1-217 60 Ex. 1-218 62 Ex. 1-219 88 Ex. 1-220 82 Ex. 1-221 73 Ex. 1-222 89 Ex. 1-223 96 Ex. 1-224 90 Ex. 1-225 98 Ex. 1-226 84 Ex. 1-227 75 Ex. 1-228 64 Ex. 1-229 60 Ex. 1-230 95 Ex. 1-231 44 Ex. 1-232 91 Ex. 1-233 93 Ex. 1-234 62 Ex. 1-235 93 Ex. 1-236 87 Ex. 1-237 84 Ex. 1-238 99 Ex. 1-239 87 Ex. 1-240 97 Ex. 1-241 101 Ex. 1-242 101 Ex. 1-243 92 Ex. 1-244 50 Ex. 1-245 78 Ex. 1-246 92 Ex. 1-247 82 Ex. 1-248 94 Ex. 1-249 94 Ex. 1-250 81 Ex. 1-251 83 Ex. 1-252 98 Ex. 1-253 49 Ex. 1-254 96 Ex. 1-255 90 Ex. 1-256 91 Ex. 1-257 89 Ex. 1-258 90 Ex. 1-259 91 Ex. 1-260 92 Ex. 1-261 97 Ex. 1-262 87 Ex. 1-263 83 Ex. 1-264 90 Ex. 1-265 100 Ex. 1-266 89 Ex. 1-267 86 Ex. 1-268 85 Ex. 1-269 89 Ex. 1-270 90 Ex. 1-271 91 Ex. 1-272 82 Ex. 1-273 92 Ex. 1-274 94 Ex. 1-275 94 Ex. 1-276 92 Ex. 1-277 97 Ex. 1-278 94 Ex. 1-279 91 Ex. 1-280 98 Ex. 1-281 77 Ex. 1-282 99 Ex. 1-283 97 Ex. 1-284 103 Ex. 1-285 100 Ex. 1-286 96 Ex. 1-287 104 Ex. 1-288 91 Ex. 1-289 98 Ex. 1-290 86 Ex. 1-291 86 Ex. 1-292 86 Ex. 1-293 33 Ex. 1-294 68 Ex. 1-295 74 Ex. 1-296 102 Ex. 1-297 94 Ex. 1-298 94 Ex. 1-299 64 Ex. 1-300 43

TABLE 27-3 Compound Percent inhibition No. (% at 1 μM) Ex. 1-301 75 Ex. 1-302 79 Ex. 1-303 100 Ex. 1-304 72 Ex. 1-305 97 Ex. 1-306 99 Ex. 1-307 60 Ex. 1-308 41 Ex. 1-309 58 Ex. 1-310 59 Ex. 1-311 83 Ex. 1-312 86 Ex. 1-313 96 Ex. 1-314 86 Ex. 1-315 81 Ex. 1-316 87 Ex. 1-317 85 Ex. 1-318 96 Ex. 1-319 42 Ex. 1-320 57 Ex. 1-321 84 Ex. 1-322 77 Ex. 1-323 87 Ex. 1-324 91 Ex. 1-325 90 Ex. 1-326 71 Ex. 1-327 81 Ex. 1-328 63 Ex. 1-329 87 Ex. 1-330 69 Ex. 1-331 75 Ex. 1-332 73 Ex. 1-333 91 Ex. 1-334 96 Ex. 1-335 73 Ex. 1-336 82 Ex. 1-337 66 Ex. 1-338 71 Ex. 1-339 40 Ex. 1-340 69 Ex. 1-341 66 Ex. 1-342 57 Ex. 1-343 51 Ex. 1-344 76 Ex. 1-345 55 Ex. 1-346 80 Ex. 1-347 55 Ex. 1-348 76 Ex. 1-349 74 Ex. 1-350 61 Ex. 1-351 81 Ex. 1-352 91 Ex. 1-353 100 Ex. 1-354 96 Ex. 1-355 98 Ex. 1-356 96 Ex. 1-357 74 Ex. 1-358 88 Ex. 1-359 69 Ex. 1-360 90 Ex. 1-361 93 Ex. 1-362 83 Ex. 1-363 77 Ex. 1-364 97 Ex. 1-365 97 Ex. 1-366 103 Ex. 1-367 105 Ex. 1-368 101 Ex. 1-369 98 Ex. 1-370 84 Ex. 1-371 90 Ex. 1-372 89 Ex. 1-373 85 Ex. 1-374 96 Ex. 1-375 85 Ex. 1-376 100 Ex. 1-377 96 Ex. 1-378 98 Ex. 1-379 84 Ex. 1-380 92 Ex. 1-381 92 Ex. 1-382 83 Ex. 1-383 83 Ex. 1-384 82 Ex. 1-385 93 Ex. 1-386 92 Ex. 1-387 93 Ex. 1-388 92 Ex. 1-389 69 Ex. 1-390 89 Ex. 1-391 82 Ex. 1-392 98 Ex. 1-393 98 Ex. 1-394 83 Ex. 1-395 90 Ex. 1-396 89 Ex. 1-397 90 Ex. 1-398 91 Ex. 1-399 55 Ex. 1-400 72 Ex. 1-401 90 Ex. 1-402 109 Ex. 1-403 102 Ex. 1-404 96 Ex. 1-405 90 Ex. 1-406 86 Ex. 1-407 85 Ex. 1-408 91 Ex. 1-409 98 Ex. 1-410 82 Ex. 1-411 90 Ex. 1-412 87 Ex. 1-413 75 Ex. 1-414 96 Ex. 1-415 94 Ex. 1-416 95 Ex. 1-417 99 Ex. 1-418 98 Ex. 1-419 98 Ex. 1-420 92 Ex. 1-421 99 Ex. 1-422 100 Ex. 1-423 96 Ex. 1-424 97 Ex. 1-425 90 Ex. 1-426 88 Ex. 1-427 95 Ex. 1-428 100 Ex. 1-429 96 Ex. 1-430 95 Ex. 1-431 99 Ex. 1-432 93 Ex. 1-433 76 Ex. 1-434 85 Ex. 1-435 87 Ex. 1-436 85 Ex. 1-437 92 Ex. 1-438 90 Ex. 1-439 81 Ex. 1-440 98 Ex. 1-441 86 Ex. 1-442 98 Ex. 1-443 101 Ex. 1-444 88 Ex. 1-445 75 Ex. 1-446 94 Ex. 1-447 98 Ex. 1-448 92 Ex. 1-449 99 Ex. 1-450 97

TABLE 27-4 Compound Percent inhibition No. (% at 1 μM) Ex. 1-451 82 Ex. 1-452 67 Ex. 1-453 94 Ex. 1-454 95 Ex. 1-455 98 Ex. 1-456 98 Ex. 1-457 94 Ex. 1-458 89 Ex. 1-459 96 Ex. 1-460 92 Ex. 1-461 95 Ex. 1-462 87 Ex. 1-463 99 Ex. 1-464 87 Ex. 1-465 80 Ex. 1-466 77 Ex. 1-467 95 Ex. 1-468 85 Ex. 2-1 88 Ex. 2-2 98 Ex. 2-3 92 Ex. 2-4 88 Ex. 2-5 97 Ex. 2-6 80 Ex. 2-7 91 Ex. 2-8 88 Ex. 2-9 82 Ex. 2-10 79 Ex. 2-11 91 Ex. 2-12 91 Ex. 2-13 87 Ex. 2-14 93 Ex. 2-15 90 Ex. 2-16 93 Ex. 2-17 87 Ex. 2-18 91 Ex. 2-19 93 Ex. 2-20 93 Ex. 2-21 93 Ex. 2-22 94 Ex. 2-23 96 Ex. 2-24 93 Ex. 2-25 96 Ex. 2-26 95 Ex. 2-27 96 Ex. 2-28 97 Ex. 2-29 95 Ex. 2-30 99 Ex. 2-31 93 Ex. 2-32 85 Ex. 2-33 91 Ex. 2-34 97 Ex. 2-35 96 Ex. 2-36 95 Ex. 2-37 91 Ex. 2-38 92 Ex. 2-39 93 Ex. 2-40 96 Ex. 2-41 93 Ex. 2-42 96 Ex. 2-43 95 Ex. 2-44 96 Ex. 2-45 95 Ex. 2-46 93 Ex. 2-47 100 Ex. 2-48 103 Ex. 2-49 93 Ex. 2-50 99 Ex. 2-51 97 Ex. 2-52 95 Ex. 2-53 97 Ex. 2-54 87 Ex. 2-55 97 Ex. 2-56 92 Ex. 2-57 94 Ex. 2-58 92 Ex. 2-59 97 Ex. 2-60 96 Ex. 2-61 92 Ex. 3-1 95 Ex. 3-2 90 Ex. 4-1 67 Ex. 4-2 81 Ex. 4-3 72 Ex. 5-1 94 Ex. 5-2 90 Ex. 6-1 91 Ex. 6-2 77 Ex. 6-3 96 Ex. 6-4 10 Ex. 6-5 97 Ex. 6-6 87 Ex. 6-7 86 Ex. 6-8 83 Ex. 6-9 85 Ex. 6-10 76 Ex. 6-11 73 Ex. 6-12 67 Ex. 6-13 81 Ex. 6-14 80 Ex. 6-15 55 Ex. 6-16 26 Ex. 6-17 32 Ex. 6-18 24 Ex. 6-19 72 Ex. 6-20 84 Ex. 6-21 85 Ex. 6-22 88 Ex. 6-23 85 Ex. 6-24 78 Ex. 6-25 49 Ex. 6-26 16 Ex. 6-27 51 Ex. 6-28 42 Ex. 6-29 69 Ex. 6-30 45 Ex. 6-31 44 Ex. 6-32 4 Ex. 6-33 68 Ex. 6-34 70 Ex. 6-35 60 Ex. 6-36 30 Ex. 7-1 97 Ex. 7-2 88 Ex. 7-3 65 Ex. 8-1 16 Ex. 9-1 29 Ex. 9-2 23 Ex. 9-3 1 Ex. 9-4 42 Ex. 9-5 3 Ex. 10-1 34 Ex. 10-2 6 Ex. 10-4 10 Ex. 11-1 96

TABLE 28-1 Compound IC₅₀ No. (nM) Ex. 1-4 19 Ex. 1-28 88 Ex. 1-70 39 Ex. 1-72 94 Ex. 1-205 59 Ex. 1-209 49 Ex. 1-225 40 Ex. 1-226 409 Ex. 1-252 87 Ex. 1-254 24 Ex. 1-255 66 Ex. 1-256 66 Ex. 1-257 75 Ex. 1-258 63 Ex. 1-259 96 Ex. 1-260 69 Ex. 1-265 24 Ex. 1-273 112 Ex. 1-274 108 Ex. 1-275 99 Ex. 1-282 77 Ex. 1-283 63 Ex. 1-284 40 Ex. 1-285 43 Ex. 1-286 61 Ex. 1-287 45 Ex. 1-288 146 Ex. 1-289 68 Ex. 1-296 15 Ex. 1-297 89 Ex. 1-298 79 Ex. 1-333 92 Ex. 1-353 43 Ex. 1-354 61 Ex. 1-355 52 Ex. 1-356 60 Ex. 1-365 56 Ex. 1-366 19 Ex. 1-367 26 Ex. 1-368 41 Ex. 1-376 22 Ex. 1-377 15 Ex. 1-378 14 Ex. 1-385 54 Ex. 1-386 48 Ex. 1-392 26 Ex. 1-393 32 Ex. 1-404 56 Ex. 1-408 72 Ex. 1-409 25 Ex. 1-440 39 Ex. 1-443 21

INDUSTRIAL APPLICABILITY

The compounds of the present invention have a superior PHD2 inhibitory effect and by means of the present invention, it becomes possible to provide pharmaceuticals that are effective for preventing or treating anemia-caused diseases and the like and this is expected to lessen the burden on patients and hence contribute to the development of the pharmaceutical industry. 

1. A compound represented by the following general formula (I′)

(wherein in formula (I′), W represents the formula —CR¹⁵R¹⁶—, the formula —CR¹¹R¹²CR¹³R¹⁴—, or the formula —CH₂CR¹⁷R¹⁸CH₂—; R¹⁵ represents a hydrogen atom, C₁₋₄ alkyl, or phenyl; R¹⁶ represents a hydrogen atom or C₁₋₄ alkyl; provided that R¹⁵ and R¹⁶, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane; R¹¹ represents a hydrogen atom, a fluorine atom, C₁₋₄ alkyl, or phenyl; R¹² represents a hydrogen atom, a fluorine atom, or C₁₋₄ alkyl; provided that R¹¹ and R¹², together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom; R¹³ represents a hydrogen atom, carbamoyl, C₁₋₄ alkyl (the C₁₋₄ alkyl is optionally substituted by one group selected from the group consisting of hydroxy, C₁₋₃ alkoxy, and di-C₁₋₃ alkylamino), halo-C₁₋₄ alkyl, phenyl, pyridyl, benzyl, or phenethyl; R¹⁴ represents a hydrogen atom, C₁₋₄ alkyl, or halo-C₁₋₄ alkyl; provided that R¹³ and R¹⁴, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane, a 4- to 8-membered saturated heterocycle containing an oxygen atom, or a 4- to 8-membered saturated heterocycle containing a nitrogen atom (the 4- to 8-membered saturated heterocycle containing a nitrogen atom is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of methyl, benzyl, phenylcarbonyl, and oxo); provided that said R¹² and R¹³, together with the adjacent carbon atoms, optionally form C₃₋₈ cycloalkane; R¹⁷ represents a hydrogen atom or C₁₋₄ alkyl; R¹⁸ represents a hydrogen atom or C₁₋₄ alkyl; provided that R¹⁷ and R¹⁸, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane; Y represents a single bond or C₁₋₆ alkanediyl (the C₁₋₆ alkanediyl is optionally substituted by one hydroxy, and one of the carbon atoms in the C₁₋₆ alkanediyl is optionally substituted by C₃₋₆ cycloalkane-1,1-diyl); R² represents a hydrogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl {the C₃₋₈ cycloalkyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl (the C₁₋₆ alkyl is optionally substituted by one phenyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and halo-C₁₋₆ alkyl), C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), and pyridyl (the pyridyl is optionally substituted by one halogen atom)], C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl)}, phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α3 of substituents), naphthyl, indanyl, tetrahydronaphthyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl [the pyrazolyl, imidazolyl, isoxazolyl, and oxazolyl are optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl and phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], thiazoyl [the thiazoyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), and morpholino], pyridyl (the pyridyl is optionally substituted by one or two groups which are the same or different and are selected from group α5 of substituents), pyridazinyl, pyrimidinyl, pyrazinyl [the pyridazinyl, pyrimidinyl, and pyrazinyl are optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl), and phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl)], benzothiophenyl, quinolyl, methylenedioxyphenyl (the methylenedioxyphenyl is optionally substituted by one or two fluorine atoms), 4- to 8-membered saturated heterocyclyl containing a nitrogen atom [the 4- to 8-membered saturated heterocyclyl containing a nitrogen atom is optionally substituted by one group selected from the group consisting of pyrimidinyl, phenyl-C₁₋₃ alkyl, C₃₋₈ cycloalkyl-C₁₋₃ alkylcarbonyl, and phenyl-C₁₋₃ alkoxycarbonyl], or the following formula (I″) [Formula 270] —CONR⁵CH₂—R⁶  (I″) [wherein in formula (I″), R⁵ represents a hydrogen atom or C₁₋₃ alkyl, and R⁶ represents phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and phenyl)], group α3 of substituents consists of hydroxy, cyano, carboxy, a halogen atom, C₁₋₆ alkyl {the C₁₋₆ alkyl is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl)], phenoxy (the phenoxy is optionally substituted by one C₁₋₆ alkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl and halo-C₁₋₆ alkyl)}, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one or two halogen atoms), C₃₋₈ cycloalkenyl (the C₃₋₈ cycloalkenyl is optionally substituted by one or two halogen atoms), phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α4 of substituents), thienyl (the thienyl is optionally substituted by one C₁₋₆ alkyl), pyrazolyl (the pyrazolyl is optionally substituted by one C₁₋₆ alkyl), isoxazolyl, thiazoyl (the thiazoyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, amino, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and C₁₋₆ alkylsulfonyl), pyrimidinyl (the pyrimidinyl is optionally substituted by one amino), quinolyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, carbamoyl, C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl), phenyl (the phenyl is optionally substituted by one group selected from the group consisting of hydroxy, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, and di-C₁₋₆ alkylamino), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), oxazolyl (the oxazolyl is optionally substituted by one or two C₁₋₆ alkyls), pyrazolyl (the pyrazolyl is optionally substituted by one or two C₁₋₆ alkyls), thiazoyl (the thiazoyl is optionally substituted by one C₁₋₆ alkyl), indazolyl (the indazolyl is optionally substituted by one C₁₋₆ alkyl), benzotriazolyl, imidazothiazolyl, and di-C₁₋₆ alkylamino], halo-C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and C₃₋₈ cycloalkyl), pyrimidinyloxy, piperazinyl (the piperazinyl is optionally substituted by one C₁₋₆ alkyl), mono-C₁₋₆ alkylaminocarbonyl (the C₁₋₆ alkyl in the mono-C₁₋₆ alkylaminocarbonyl is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, di-C₁₋₆ alkylamino, pyridyl, phenyl, and 2-oxopyrrolidinyl), di-C₁₋₆ alkylaminocarbonyl (where the two C₁₋₆ alkyls in the di-C₁₋₆ alkylaminocarbonyl, together with the adjacent nitrogen atom, optionally form a 4- to 8-membered saturated heterocycle containing a nitrogen atom), C₁₋₆ alkylsulfanyl, and C₁₋₆ alkylsulfonyl; group α4 of substituents consists of carboxy, cyano, hydroxy, sulfamoyl, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, di-C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkylsulfonyl, mono-C₁₋₆ alkylaminosulfonyl (the C₁₋₆ alkyl in the mono-C₁₋₆ alkylaminosulfonyl is optionally substituted by one hydroxy), and di-C₁₋₆ alkylaminosulfonyl; group α5 of substituents consists of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl) and phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], halo-C₁₋₆ alkoxy, phenyl (the phenyl is optionally substituted by one group selected from group α6 of substituents), pyridyl, phenoxy [the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one phenyl), and halo-C₁₋₆ alkoxy], pyridyloxy (the pyridyloxy is optionally substituted by one C₁₋₆ alkyl), and phenylsulfanyl (the phenylsulfanyl is optionally substituted by one halogen atom); group α6 of substituents consists of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy; Y⁴ represents C₁₋₄ alkanediyl; R³ represents a hydrogen atom or methyl; R⁴ represents —COOH, —CONHOH, or tetrazolyl); or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1 wherein in the aforementioned general formula (I′), Y⁴ is methanediyl, R³ is a hydrogen atom, R⁴ is —COOH, or a pharmaceutically acceptable salt thereof.
 3. The compound according to claim 2 wherein in the aforementioned general formula (I′), W is the formula —CR¹⁵R¹⁶, and the compound is represented by general formula (I′-1):

(wherein in formula (I′-1), R¹⁵ is a hydrogen atom, C₁₋₄ alkyl, or phenyl, R¹⁶ is a hydrogen atom or C₁₋₄ alkyl, provided that R¹⁵ and R¹⁶, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane), or a pharmaceutically acceptable salt thereof.
 4. The compound according to claim 2 wherein in the aforementioned general formula (I′), W is the formula —CR¹¹R¹²CR¹³R¹⁴—, and the compound is represented by general formula (I′-2):

(wherein in formula (I′-2), R¹¹ is a hydrogen atom, a fluorine atom, C₁₋₄ alkyl, or phenyl, R¹² is a hydrogen atom, a fluorine atom, or C₁₋₄ alkyl, provided that R¹¹ and R¹², together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom; R¹³ is a hydrogen atom, carbamoyl, C₁₋₄ alkyl (the C₁₋₄ alkyl is optionally substituted by one group selected from the group consisting of hydroxy, C₁₋₃ alkoxy, and di-C₁₋₃ alkylamino), halo-C₁₋₄ alkyl, phenyl, pyridyl, benzyl, or phenethyl; R¹⁴ is a hydrogen atom, C₁₋₄ alkyl, or halo-C₁₋₄ alkyl, provided that R¹³ and R¹⁴, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane, a 4- to 8-membered saturated heterocycle containing an oxygen atom, or a 4- to 8-membered saturated heterocycle containing a nitrogen atom (the 4- to 8-membered saturated heterocycle containing a nitrogen atom is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of methyl, benzyl, phenylcarbonyl, and oxo), provided that the aforementioned R¹² and R¹³, together with the adjacent carbon atoms, optionally form C₃₋₈ cycloalkane), or a pharmaceutically acceptable salt thereof.
 5. The compound according to claim 4 wherein in the aforementioned general formula (I′-2), Y is a single bond or C₁₋₆ alkanediyl (one of the carbon atoms in the C₁₋₆ alkanediyl is optionally substituted by C₃₋₆ cycloalkane-1,1-diyl), R² is C₃₋₈ cycloalkyl {the C₃₋₈ cycloalkyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl (the C₁₋₆ alkyl is optionally substituted by one phenyl), phenyl (the phenyl is optionally substituted by one halo-C₁₋₆ alkyl), C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl), and pyridyl (the pyridyl is optionally substituted by one halogen atom)], C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, and halo-C₁₋₆ alkyl)}, phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from the aforementioned group α3 of substituents), naphthyl, indanyl, tetrahydronaphthyl, pyrazolyl [the pyrazolyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl and phenyl (the phenyl is optionally substituted by one C₁₋₆ alkyl)], imidazolyl (the imidazolyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl and phenyl), isoxazolyl [the isoxazolyl is optionally substituted by one phenyl (the phenyl is optionally substituted by one halogen atom)], oxazolyl (the oxazolyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of C₁₋₆ alkyl and phenyl), thiazoyl (the thiazoyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl, phenyl, and morpholino), pyridyl (the pyridyl is optionally substituted by one or two groups which are the same or different and are selected from the aforementioned group α5 of substituents), pyridazinyl [the pyridazinyl is optionally substituted by one C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl)], pyrimidinyl [the pyrimidinyl is optionally substituted by one group selected from the group consisting of halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, and phenoxy (the phenoxy is optionally substituted by one C₁₋₆ alkyl)], pyrazinyl [the pyrazinyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl) and phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl)], benzothiophenyl, quinolyl, or methylenedioxyphenyl (the methylenedioxyphenyl is optionally substituted by one or two fluorine atoms), or a pharmaceutically acceptable salt thereof.
 6. The compound according to claim 5 wherein in the aforementioned general formula (I′-2), R¹¹ is a hydrogen atom, R¹² is a hydrogen atom, R¹³ is a hydrogen atom, R¹⁴ is a hydrogen atom, Y is methanediyl, R² is phenyl {the phenyl is substituted by one group selected from the group consisting of phenyl [the phenyl is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of carboxy, cyano, hydroxy, sulfamoyl, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, di-C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkylsulfonyl, mono-C₁₋₆ alkylaminosulfonyl (the C₁₋₆ alkyl in the mono-C₁₋₆ alkylaminosulfonyl is optionally substituted by one hydroxy), and di-C₁₋₆ alkylaminosulfonyl], pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of carboxy, hydroxy, amino, a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and C₁₋₆ alkylsulfonyl), phenoxy (the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), and pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, and C₃₋₈ cycloalkyl), and may further be substituted by one halogen atom}; pyridyl {the pyridyl is substituted by one group selected from the group consisting of phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyl, phenoxy [the phenoxy is optionally substituted by one or two groups which are the same or different and are selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy (the C₁₋₆ alkoxy is optionally substituted by one phenyl), and halo-C₁₋₆ alkoxy], and pyridyloxy (the pyridyloxy is optionally substituted by one C₁₋₆ alkyl), and may further be substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl}; or pyrazinyl which is substituted by one phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and C₃₋₈ cycloalkyl), or a pharmaceutically acceptable salt thereof.
 7. The following compound according to claim 1: N-{[4-hydroxy-2-oxo-1-(4-phenoxybenzyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; N-[(4-hydroxy-1-{[6-(4-methylphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-({4-hydroxy-2-oxo-1-[(6-phenoxy-3-pyridinyl)methyl]-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-({1-[4-(4-fluorophenoxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-({4-hydroxy-1-[4-(4-methylphenoxy)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-[(1-{[6-(4-cyanophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-({4-hydroxy-2-oxo-1-[4-(2-pyrimidinyloxy)benzyl]-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-[(1-{[6-(4-fluorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{[6-(4-chlorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-{[4-hydroxy-2-oxo-1-({6-[4-(trifluoromethyl)phenoxy]-3-pyridinyl}methyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; N-[(4-hydroxy-1-{[6-(3-methylphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{[6-(3-fluorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-({4-hydroxy-1-[4-(3-methylphenoxy)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-({1-[4-(3-fluorophenoxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-[(1-{[5-(4-fluorophenoxy)-2-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(4-hydroxy-1-{[5-(4-methylphenoxy)-2-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-({1-[4-(4-chlorophenoxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-[(4-hydroxy-1-{4-[(6-methyl-3-pyridinyl)oxy]benzyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{[6-(2-fluorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(4-hydroxy-1-{[6-(2-methylphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-({1-[4-(2-fluorophenoxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-({4-hydroxy-1-[4-(2-methylphenoxy)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-[(1-{[6-(3-chlorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-{[4-hydroxy-2-oxo-1-({6-[3-(trifluoromethyl)phenoxy]-3-pyridinyl}methyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; N-({4-hydroxy-1-[4-(3-methoxyphenoxy)benzyl]-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-{[4-hydroxy-2-oxo-1-({6-[3-(trifluoromethoxy)phenoxy]-3-pyridinyl}methyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; N-[(1-{4-[(5-fluoro-2-pyridinyl)oxy]benzyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{4-[(5-chloro-2-pyridinyl)oxy]benzyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{[6-(4-cyclopropylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(4-hydroxy-1-{4-[(5-methyl-2-pyridinyl)oxy]benzyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-{[4-hydroxy-2-oxo-1-(4-{[5-(trifluoromethyl)-2-pyridinyl]oxy}benzyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; N-{[4-hydroxy-1-({5-methyl-6-[(6-methyl-3-pyridinyl)oxy]-3-pyridinyl}methyl)-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; N-[(1-{[5-(4-chlorophenoxy)-2-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(4-hydroxy-1-{[6-(3-methoxyphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{4-[(6-chloro-3-pyridinyl)oxy]benzyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-{[4-hydroxy-2-oxo-1-({5-[4-(trifluoromethyl)phenoxy]-2-pyridinyl}methyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; N-{[4-hydroxy-2-oxo-1-(4-{[6-(trifluoromethyl)-3-pyridinyl]oxy}benzyl)-1,2,5,6-tetrahydro-3-pyridinyl]carbonyl}glycine; N-[(1-{[6-(3-chloro-4-methylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{[6-(3-fluoro-4-methylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{[6-(4-fluoro-3-methylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{[6-(4-ethylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-1-{[6-(4-propylphenoxy)-3-pyridinyl]methyl}-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(4-hydroxy-1-{[6-(4-isopropylphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(4-hydroxy-1-{[5-(4-methylphenoxy)-2-pyrazinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-({1-[4-(3,4-dimethylphenoxy)benzyl]-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl}carbonyl)glycine; N-[(1-{[5-chloro-6-(4-methylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{[5-fluoro-6-(4-methylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{4-[(5-cyclopropyl-2-pyridinyl)oxy]benzyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(4-hydroxy-1-{[2-(4-methylphenoxy)-5-pyrimidinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{[6-(4-chlorophenoxy)-5-methyl-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; N-[(1-{[5-(4-chlorophenoxy)-2-pyrazinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine; or N-[(1-{[5-(4-cyclopropylphenoxy)-2-pyrazinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine, or a pharmaceutically acceptable salt thereof.
 8. The compound according to claim 1, having the aforementioned general formula (I′), wherein W is the formula —CR¹¹R¹²CR¹³R¹⁴ and the compound is represented by general formula (I):

(wherein in formula (I), R¹¹ is a hydrogen atom, C₁₋₄ alkyl, or phenyl, R¹² is a hydrogen atom or C₁₋₄ alkyl, provided that R¹¹ and R¹², together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom; R¹³ is a hydrogen atom, C₁₋₄ alkyl, halo-C₁₋₄ alkyl, phenyl, benzyl, or phenethyl, R¹⁴ is a hydrogen atom or C₁₋₄ alkyl, provided that R¹³ and R¹⁴, together with the adjacent carbon atom, optionally form C₃₋₈ cycloalkane or a 4- to 8-membered saturated heterocycle containing an oxygen atom, provided that the aforementioned R¹² and R¹³, together with the adjacent carbon atoms, optionally form C₃₋₈ cycloalkane; Y is a single bond or C₁₋₆ alkanediyl (one of the carbon atoms in the C₁₋₆ alkanediyl is optionally substituted by C₃₋₆ cycloalkane-1,1-diyl); R² is C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one group selected from the group consisting of phenyl and benzyl), phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α1 of substituents), naphthyl, indanyl, tetrahydronaphthyl, pyrazolyl [the pyrazolyl is substituted by one phenyl (the phenyl is optionally substituted by one C₁₋₆ alkyl) and may further be substituted by one C₁₋₆ alkyl], imidazolyl (the imidazolyl is substituted by one phenyl), isoxazolyl [the isoxazolyl is substituted by one phenyl (the phenyl is optionally substituted by one halogen atom)], oxazolyl (the oxazolyl is substituted by one phenyl and may further be substituted by one C₁₋₆ alkyl), thiazoyl (the thiazoyl is substituted by one phenyl), pyridyl [the pyridyl is substituted by one group selected from the group consisting of phenyl, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, cyano, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), and phenylsulfanyl (the phenylsulfanyl is optionally substituted by one halogen atom)], pyrimidinyl (the pyrimidinyl is substituted by one group selected from the group consisting of cyclohexyl and phenyl), benzothiophenyl, quinolyl, or methylenedioxyphenyl (the methylenedioxyphenyl is optionally substituted by one or two fluorine atoms); group α1 of substituents consists of a halogen atom, C₁₋₆ alkyl {the C₁₋₆ alkyl is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl, phenyl, and C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one C₃₋₈ cycloalkyl (the C₃₋₈ cycloalkyl is optionally substituted by one C₁₋₆ alkyl)]}, halo-C₁₋₆ alkyl, C₃₋₈ cycloalkyl, phenyl (the phenyl is optionally substituted by one to three groups which are the same or different and are selected from group α2 of substituents), thienyl, pyrazolyl (the pyrazolyl is optionally substituted by one C₁₋₆ alkyl), isoxazolyl, thiazoyl (the thiazoyl is optionally substituted by one or two C₁₋₆ alkyls), pyridyl (the pyridyl is optionally substituted by one group selected from the group consisting of C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), quinolyl, C₁₋₆ alkoxy [the C₁₋₆ alkoxy is optionally substituted by one group selected from the group consisting of C₃₋₈ cycloalkyl and phenyl (the phenyl is optionally substituted by one group selected from the group consisting of a halogen atom and C₁₋₆ alkyl)], halo-C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₃₋₈ cycloalkoxy, phenoxy (the phenoxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, C₁₋₆ alkoxy, and halo-C₁₋₆ alkoxy), pyridyloxy (the pyridyloxy is optionally substituted by one group selected from the group consisting of a halogen atom, C₁₋₆ alkyl, and halo-C₁₋₆ alkyl), and C₁₋₆ alkylsulfanyl; group α2 of substituents consists of a halogen atom, cyano, hydroxy, C₁₋₆ alkyl, halo-C₁₋₆ alkyl, phenyl, C₁₋₆ alkoxy, halo-C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl, and di-C₁₋₆ alkylaminosulfonyl), or a pharmaceutically acceptable salt thereof.
 9. A medicine comprising the compound according to any one of claims 1 to 8 and 13 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient.
 10. A method for inhibiting PHD2 comprising administering to a subject in need thereof an effective amount of the compound according to any one of claims 1 to 8 and 13 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient.
 11. A method of promoting production of EPO comprising administering to a subject in need thereof an effective amount of the compound according to any one of claims 1 to 8 and 13 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient.
 12. A method for preventing or treating anemia comprising administering to a subject in need thereof an effective amount of the compound according to any one of claims 1 to 8 and 13 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient.
 13. The compound of claim 1 which is N-[(1 {[6-(4-chlorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5.6-tetrahydro-3-pyridnyl)carbonyl]glycine, or a pharmaceutically acceptable salt thereof.
 14. The compound of claim 1 which is N-[(1-{[6-(4-cyclopropylphenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine, or a pharmaceutically acceptable salt thereof.
 15. The compound of claim 1 which is N-[(4-hydroxy-1-{[6-(3-methylphenoxy)-3-pyridinyl]methyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine, or a pharmaceutically acceptable salt thereof.
 16. The compound of claim 1 which is N-[(1-{[6-(3-fluorophenoxy)-3-pyridinyl]methyl}-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine, or a pharmaceutically acceptable salt thereof.
 17. The compound of claim 1 which is N-[(4-hydroxy-1-{4-[(6-methyl-3-pyridinyl)oxy]benzyl}-2-oxo-1,2,5,6-tetrahydro-3-pyridinyl)carbonyl]glycine, or a pharmaceutically acceptable salt thereof. 